Rodrigo de Bastidas, was a leader of an expedition of exploration, that set sail from Spain in October, 1500, in two ships. Vasco Nuñez de Balboa was a  members of that expedition. They reached what is now know has Venezuela, and continued sailing west, along skirting the coast of present day Colombia. They sailed past el Cabo de Vela, and reaching el Golfo de Darien in 1501. They sailed south, once they enter the gulf, believing that they had found the passage to Cathay. Sailing some distance into the gulf, they noticed the water was not salty and shallow, realizing that it was not the passage they were seeking.  He then turned north, and continued exploring the area. They saw on the west, that there was a large river (Atrato River) that flowed into the bay, but they did not land to explore it. They then  continued north-west, along the coast as far as El Retrete, possibly as far as the site were Nombre de Diós, would be founded years later, and possibly as far as the future site of Porto Bello. Bastidas did not name these two, sites, and it would be up to others, to name them. Because of this voyage, Bastidas has been given the credit for the discovery of Panamá in 1501.

Christopher Columbus sailed on his fourth and last voyage of exploration, from Cadiz on May 11, 1502. With him on this voyage was Bartolomé Columbus, his brother, and his second son, Fernando. Stopping off in Española, he had the opportunity to confer with Bastidas, and examine his charts. He sailed west, past Cuba, and landed on the northern coast of Honduras, east of the Yucatan. Skirting the coast of Tierra Firme, he sailed east over the Honduras hump and then south east. He continued skirting the coast of Central America, past Honduras, Nicaragua and Costa Rica. On October 6, 1502, they entered Almirante Bay, in what is now known as Boca del Toro, Panamá. Columbus continued along the coast, eastward, past the Chiriqui Lagoon and Veraguas, past the Chagres River, and the Bay of Limon, until he reached a beautiful bay, that he named Puerto Bello on November 2nd, 1502. They were forced to stay there 7 days, due to inclement weather. By November 24, he had  reached the most eastward he would travel on the coast of Panama, at a harbor, that he named El Retrete. This was also the last place that appeared on Bastidas' chart or the area.

In 1508, the King of Spain, and the Council of the Indies became interested in colonize Tierra Firme.  Up to then, they had been preoccupied with the wars in Spain and had neglected the New World. In Spain, at the time, were to men interested in exploring and colonizing the newly discovered lands. The person most interested in colonizing the area, was Alonso de Ojeda. Unfortunately, he was not a rich man, and lacked contact with the Spanish Court. The did have the support of  Juan de la Cosa, who had been with Columbus on some of his voyages, and had become famous with many friends in the Spanish Court, offered financial support. With the help of Juan Rodriquez de Fonseca, Bishop of Palencia, who managed of the Affairs of the Indies, he was able to get an audience in Court, to discuss his proposals.

There was another applicant for the privilege of colonizing Tierra Firme, Don Diego de Nicuesa. He had the advantage not only being richer than Ojeda, but he was also, much more polished. He held the office of The Royal Carver, wore the fanciest clothes ever seen in Madrid, was very popular with the ladies at Court, and was a gentleman of unquestioned integrity and valor; but, a terrible leader of men. 

The King proceeded to name both men, governors of the area. Alonso de Ojeda was given the area called Nueva Andalucia, while Diego de Nicuesa was given Castilla del Oro. At that time, there was no clear cut boundary between Nueva Andalucia and Castilla del Oro. The King left this detail to Ojeda and Nicuesa to figure out for themselves.

In the fall of 1509 the two governors met in Española and started quarreling right away. The king had further complicated matters, by giving them, as a joint source of provisions, the Island of Jamaica. This upset the governor of Española, Diego Colon, the son of the Great Admiral. Diego claimed all lands discovered by his father, which included Jamaica. This made him so hostile to the two new governors, that instead of helping them with ships and men, as the king had ordered, he did all he could to hinder and impede them. He also did everything he could to fan the fire of jealousy between them. With all of the fighting between themselves, Ojeda soon lost his cool and challenged Nicuesa to a duel. With the mediation of Juan de la Cosa, bloodshed was averted and they agreed to accept the Darien River, now called the Atrato River, as the boundary between their provinces.

The truce that existed between them was very precarious. Nicuesa, being the more affluent of the two, was able to outbid Ojeda for ships and equipment. This was  counterbalanced by Ojeda's experience in the area, his reputation and personal charisma  attracted the best and most able of the volunteers. Among them were two who would later paint their names in letters of blood and fire on the chronicle of the Americas, Hernado Cortes and Francisco Pizarro. Ojeda was able to enlist the Bachelor of Law, Martin Fernandez de Enciso to his side. This attorney had amassed a fortune in the few years of colonial practice. But he had not realized the fact that it is easier to get money from adventurers than by adventures. Like so many another he fell under Ojeda's  charm. Ojeda promise to make him "Alcalde Major", Chief Justice of the soon to be conquered vice-royalty of Nueva Andalusia, and he turned offered Ojeda his fortune.

On November 12, 1509, Ojeda set sailed from Española, with two ships, two brigantines, three hundred men and twelve brood mares. Hernando Cortes was not able to sail with him, due to a wound in his knee and was left behind. On November 14, 1509, Nicuesa set sail with two large ships, two brigantines, a caravel, seven hundred men and six horses. Nicuesa led a better equipped and lager expedition. His force was made up mostly of men fresh from Spain, lacking experience, and not  hardened for the work before them. Martin Fernandez de Enciso remained behind in Española, recruiting more men and buy supplies. He was to follow Ojeda, once this was done.

Shortly after leaving Española, Ojeda's fleet reached his unconquered, new vice-royalty, near the present city of Cartagena, Colombia. He went ashore with part of his force to take possession of the land, and establish his authority in the area. He proceeded to wave the Spanish flag, erect a cross at the point where he set foot on dry land. The Spaniards that had previously visited this coast had come to trade. The Indians in the area, came to the shore with hospitable intention and prepared and willing to trade. But when Ojeda, and the priest that he had with him, informed the Indians, that they had to renounce their king, and swear allegiance to the King of Spain, and Spanish God, they said, no. Ojeda ordered that they be taken by force, and a battle quickly ensued where the Indians were defeated.  Ojeda was excited after defeating the natives on the beach and he ordered the pursuit of the natives that had escaped into the jungle. After about an hour, they came to a large Indian village and the Spaniards scattered in all directions, looking for booty. At that point, the natives who had taken refuge in the jungle, turned around and attacked. The Spaniards, more interested in finding gold and pearls, let down their guard and most of them fell during the first surprise attack. These Indians had a deadly weapon that the Spaniards could not defend themselves against, poison arrows and darts. Juan de la Cosa was one of the first, to succumb to the deadly arrows.

From that point the beginning of the end of Ojeda new settlement of San Sebastian was guaranteed. The colonist went hungry and thirsty. They could not venture out of the settlement, for risk of being attacked by the natives. The Indians were keeping an eye on the community, and when ever a Spaniard wondered outside of their palisades, he was shot. Ojeda himself was shot, but he was lucky that he was hit, with an arrow that was not poisoned. When the opportunity arise, Ojeda set sail back to Española, to find out what had happened to Enciso. He instructed the surviving men, that if he or Enciso did not return within 50 days, they should take the last two surviving ship and return to Española. 

The boat that Ojeda had boarded for this transit to Española was commanded by a pirate who tried to take all of Ojeda's treasures, that he was returning to Española with, to buy supplies. The ship was also hit by a hurricane and forced off course, ship wreaked in Cuba, where Ojeda spent months, before getting back to Española.

Enciso sailed from Española on September 1, 1510 with 2 ships, a caravel and a brigantine, 150 men, 12 mares, some stallions, pigs to breed, plenty of food and clothes, weapons and 2 stowaways, to join Ojeda. He was unaware of the trouble and hard time, that had fallen on San Sebastian. On his ship, he carried a stow-a-way, Vasco Nuñez de Balboa and his dog Leoncito, who was not allowed to leave Española, since he was in debt.

At the end of the 50 days, the survivors started the evacuation of San Sebastian. When the sailed off, on the ships hit a reef, and went down, with the loss of all lives. The second ship, piloted by Francisco Pizarro was spotted by Enciso, who was approaching the area. He ordered Pizarro to turn around, and would not believe the Ojeda's settlement was a failure. Pizarro had present the written document, signed by Ojeda, giving orders, to wait for 50 days, and then return to Española, if relief did not come. Enciso, fearful of losing his investment in the venture, ordered Pizarro to turn around, and try to re-establish the community. 

When they return to San Sebastian, the found nothing but burned buildings. When the natives saw that the Spaniards had abandoned the community, proceeded to burn every thing to the ground. The continued sailing further west, hoping to find a more suitable place to rebuild San Sebastian. But, Enciso, believing that he knew everything, and against the recommendation of Balboa and his pilot, sailed his ship into a reef, and lost everything. They lost all of the provisions, that were on his ship, which was the largest vessel of the expedition. Since all of their food was gone, they were forced to live off the land, hunting peccary and eating fruits. Wanting to get (steal) food from the natives, Enciso, ordered and led his party inland, hoping to capture a native village, and take their food. But the natives were prepared, and attacked the Spaniards as they approached with poison arrows forcing them to retreat. 

At this point, Enciso became dishearten, until Balboa, told him about the land on the opposite side of the bay, which he had visited when he was with Bastidas. He told him, that the Indians on that side of the bay, did not have poison arrows, and were friendly to the Spaniards. 

Vasco Nuñez de Balboa directed the Spaniards to their first secure foothold on Tierra Firme (Continent of America). His suggestion to try the western shore of the Gulf of Darien was accepted by acclamation. Enciso saw this option as another way to salvage his investment in the expedition. Not being able to fit all of the men into the one remaining brigantine, some of the men were left at San Sebastian, in a hastily reconstructed stockade for their defense. They then crossed the gulf, where Balboa directed them to a territory ruled by the Cacique Cemaco.

Cemaco remembered the problems with the Spaniards the first time they visited his territory. As soon as he saw the long boats approaching land, he sent the women and children into the jungles to hide. After they were protected, he went to the beach with 500 warriors to meet the invaders.

When Enciso landed, he proceeded with the Spanish custom, of proclaiming all of the land for the King of Spain and the Holy Catholic Church. He then read another proclamation where he promises to baptize all of the heathens. He promised the Virgin Mary, that this heathen town would be hers in name, if she would make it his in substance, along with Cemaco's gold, he will build on Cemaco's land a church, and dedicate it to her adored image, Antigua of Seville. He also promised, that if she would do that for him, he would take a pilgrimage to her holy shrine. While all of this was going on, more men were disembarking from the ships. This ceremony had the function of legalizing, in the Spaniards eyes,  what ever they did against the natives, who were not Christians.

Once all the formalities were dispensed with, the Spaniards yelled their war cry "Santiago y a ellos" and attacked the natives with such ferocity, that they quickly routed them. They chased the fleeing natives to Cemaco's village and captured it. Making good his promise, he re-christened the village, "Santa Maria de la Antigua del Darien". With in the next couple of days, they had confiscated large quantities of food and over $50,000 in gold from the natives.

The settlers became upset with these new laws, and some talked about revolts, arresting Enciso and sending back to Santo Domingo, or killing him, etc. As the rhetoric increased in fervor, and the hostility towards Enciso was at its peak, Vasco Nuñez de Balboa, advised the settlers to calm down, that there were other recourses they could follow. He informed them, that they were now in the province of Castilla del Oro, not Nueva Andalusia. That Castilla del Oro, was the domain of Nicuesa, not Ojeda and Enciso who had legal rights only in Nueva Andalusia. 

The colonist's immediately held elections for new leaders. They elected two Alcaldes (Mayors), Vasco Nuñez de Balboa and Martín Zamudio. Unfortunately for the new community, new leaders did not mean an end to its problems. They still had to build a city, with roads, churches, houses, parks, and fortifications. They had to plant crops so they could feed themselves in the future.

Sometime on November, 1510, the settlement of Antigua heard cannon fire across the bay. They started a large fires to attract attention of the ship in the bay. Enciso became very excited, thinking that it was Ojeda, coming back with reinforcements. It would mean that with Ojeda back, Enciso would get his old  position back.

As the ship was under the command of Rodrigo Enriquez de Colmenares and he was bringing provisions and additional men for Nicuesa, who was somewhere in Castilla del Oro. Colmenares left some of the provisions in Antigua, and then left to continue his journey to find Nicuesa. Two members of the community went with him, to invite Nicuesa to come to Antigua, and rule the colony.

When Colmenares finally found Nicuesa, he was at Nombre de Diós, and there was only a small handful of men left from the seven hundred that left Española. Nicuesa was excited to hear that there was a successful and rich settlement in his land, Castilla del Oro, and he was invited to go and rule it. He immediately made plans for going there, and after a little too much to drink, let the emissaries know that he intended to rule with an iron fist, and arrest the leaders of the community, for trespassing on his land. He advised them that he would confiscate all of the treasures illegally collected by the residents of Antigua, in his land. He then sent the emissaries back with instruction, to get everything ready, for when he arrived.

When they got back to Antigua, they informed the councils of all they saw and heard. Both from Nicuesa himself and some of the surviving members of his expedition, who really hated him. The citizens of Antigua voted to keep Nicuesa out of their settlement. When he arrived in Antigua,  he was warned that they did not want him, and to return to from where he came. He landed anyway, and was promptly arrested. In March, 1511, he was put on the most rotten ship, and set off to sea along with 17 of his most ardent supporters. Nicuesa repented and pleaded with the residents, to let him stay, and he would work like everybody else, and give up his title as governor, but the residents did not believe him, and sent him off  and he was never heard from again.  

Shortly after Nicuesa's departure, Enciso tried to instigate a revolt and was arrested. He was convicted, but set free by Vasco Nuñez de Balboa., with the understanding that he would leave for Spain on next available ship.

On July 27, 1513 a new governor was appointed by the King of Spain, to Castilla Aurifica (Golden Castle), the new name for the area from Antigua extending as far as Veraguas. Pedro Arias de Ávila (Pedrarias), was 70 years old and undertook his new assignment with the vitality of a 30 year old. He was sent to Antigua  to replace Balboa, after the King heard the story of Balboa's actions against Nicuesa and Enciso.

On June 30, 1514, Pedrarias arrived at Antigua, and formally took control of the settlement. On his fleet, there were not only soldiers, but some colonist that were there to begin the settlement of Castilla Aurifica. Pedrarias asked Balboa  to prepare a written report on all of his experiences and events that had occurred in the colony. Balboa prepared the document giving complete details of all that had transpire during his command of the region. No sooner did Balboa give the report to Pedrarias, when he turned against him and had him arrested.  Balboa was spared harsh punishment, had it not been for the bishop and the alcalde, who defended him, and he had the support of the populace. Pedrarias had to release him or face an uprising, with the orders that he could not leave Antigua.

Pedrarias first year at Antigua was a disaster. Many of his men died, over 700 during the first four months, of disease. Famine became a problem, since most of the food brought from Spain, spoiled in the humid climate.  Over a hundred colonist, abandoned Antigua and returned to Cuba, out of fear for their life and health. King Ferdinand had ordered that settlements be established at different places in the new province and the exploration of the South Sea, forcing Pedrarias to release Balboa, and make use of his services. Pedrarias' forces had little luck, in establishing settlements, because of their bad  treatment the natives, and stealing their gold. The natives were always attacking their settlements. Even the caciques that Balboa had peace treaties with, were abused by the new Spanish government.

In 1515, Captain Antonio Tello de Guzmám, under order of Pedrarias, was exploring the western coasts of the South Sea, when he came upon a native village of fishermen. The natives called themselves and their village, Panamá (many fish). Pedrarias ordered that the hamlet of Panamá be made an outpost to assist in the exploration of all the lands, bordering the South Sea. On the morning of August 15, 1519, with much fanfare, Pedrarias formally founded the city of Nuestra Señora de la Asunción de Panamá for Queen Juana de Castilla, and her son, King Carlos V. Two years before, in January 1517, Pedrarias had ordered the arrest, trial and execution (he was beheaded on January of Vasco Nuñez de Balboa. 

When Pedrarias had confirmation that the new governor was coming, he proposed that the city council at Antigua, that they move the capital from Antigua to Panamá, because the climate was healthier. The council rejected his proposition, just as Pedrarias hoped they would. He then took off, with his cronies to Panamá and establish himself there, free from Antigua and out of the jurisdiction of the new governor. They moved southward, over the mountains with all of the treasure they could get, and all of the troops they could muster. He then established Panamá as the capital of the South Sea.

In May of 1520, the new governor, Lope de Sosa and his entourage of 300 men arrived in Antigua. That night, Sosa became ill in his cabin, and died, before he had a chance to disembark at his new post. This provided a reprieve for Pedrarias to continue doing as he pleased, until a new governor could be appointed and sent to Antigua. On the ship with Sosa, was the Veedor and Escribano General of Antigua, Oviedo. As veedor, Oviedo refused to let Pedrarias move the capital from Antigua and Pedrarias, just moved out. He allowed Oviedo to govern the town of Antigua anyway he wanted, knowing full well, that the people in Antigua, would not like to new rules wanted by clergy and King.

Oviedo presented to the city council his credentials in November, 1521. He was upset with the way the Spaniards had ruled Antigua and started his reforms immediately. The first laws he passed, had the desired effect that Pedrarias was waiting for and wanted. Oviedo made it illegal to swear, blaspheme and gamble. He also made it illegal the keeping of mistresses and trading in Indian children. These were rules, that the wild conquistadors, were not going to abide by. As soon as these rules were announced, people began to immigrate to Panamá. There were some positives accomplished by Oviedo. He opened up the mines, built ships, and made peace with the Indians. He had the misfortune of losing his wife and son, to disease in Antigua. He also sent the bachiller Corral, one of Pedrarias' cohorts to Spain in chains. Pedrarias still had many friends in Spain, and Corral returned to Antigua, and Pedrarias named him to replace Oviedo as veedor. When Corrals appointment was announced, Oviedo started using another one of the titles he had been granted by the King, Regidor en Perpetuo. There were several attempts on Oviedo's life, the last being on July 3, 1523. After that attempt, he took off to Cuba and then Spain.

With the departure of Oviedo, the population of the town, continued to decrease at a faster rate. Eventually Diego Ribero, the last Spaniard, resident in Antigua was killed by Indians in September, 1524. They killed his whole family, and burned the town to the ground allowing the jungle to reclaim what was once a thriving community.