In 1575 Oxenham returned to Panamá, with 75 men, some of which were veterans of Drake's earlier Panamá expeditions, and a 120 ton ship. This time, he was in command of the expedition. On his arrival at Port Pheasant in the Darien, the old secret hideout of Drake, Diego, a Cimarron chieftain who had befriended Drake during their earlier campaigns, went to Oxenham's camp to offer his services. (The Cimarron's were groups of escaped Negro slaves, some which had intermarried with the native Indians of the area. They were always at war with their old Spanish masters. With the help of the native Indians who also hated the Spaniards, always welcomed an opportunity to join with the pirates and buccaneers, to take up arms against the Spanish. The buccaneers became very dependent on the Cimarron's to supply them with food, guides, and mercenaries, in their excursions into Spain's Main, all over the Americas.) He also informed Oxenham that it would not be as easy as before, to capture a gold train, as they now crossed the Isthmus. The Spaniards, were sending all gold trains with a large contingent of soldiers and lookouts, has a consequence of Drake's previous raids. Diego still offered to assist Oxenham, with as many Cimarron's as he needed to take up the attacks on the Spaniards. When informed of this, Oxenham gave up on the idea of capturing a Gold Train, and decided to cross the Isthmus and capture Spanish ships in the South Sea.

Oxenham's men beached their ship, and covered it with branches and foliage to camouflage it . They buried their cannons, except for two small one, and then set out across the Isthmus with all his men and a large number of Cimarron and Indian allies. To avoid direct confrontation with the Spaniards, and to keep the Spaniards from learning of their presence, they used a jungle trail, known to the Cimarron's, that was parallel with the Treasure Road and some distance from it, to cross the Isthmus.

When they crossed over the cordillera, they found a river to reach the South Sea. The Cimarron's attacked a lumber production camp in the Golfo de San Miguel. There they stole tools and lumber so that Oxenham could build a 45 foot pinnace (a light boat propelled by oars and one or two masts outfitted with lanteens sails, used to transport men from the ship to land. Most ships carried one of these, and they were used as their life boats. ). The English, with the help of 6 of the Cimarron's,  sailed down the river, through the Gulf de San Miguel, and became the first Englishmen to sail the South Sea.  They set course to the Pearl Islands, and within 10 days, captured a Spanish ship from Quito, with 60,000 pesos of gold, wine and bread  on board. A couple of days later, the captured another Spanish ship, for Lima, with 100,000 pesos of silver ingots.  The Spanish never expected their Merchant ships, sailing the South Sea, to be attacked by pirates. Therefore, they were not required to travel in fleets, under the protection of Galleons. Most of the merchant ships did not carry heavy armaments or soldiers. 

They landed on the Pearl Island, hoping to secure some pearls, but found very little. The pirates looted the Pearl Islands and  tortured a Franciscan friar before killing him. They left the Islands, back in the direction of the Gulf of San Miguel, and released the two ships he had captured. The islanders, immediately sent a boat to Panamá to warn the Governor.

The governor of Panamá, ordered all available ships to be outfitted with cannons and soldiers, to protect the city and search the waters in the Gulf of Panamá for the pirates. One of the patrols, commanded by Juan de Ortega, consisting of four barques and 100 men. Ortega sailed directly to the Pearle Island, where he was informed of the direction the pirates took off in. Later, he came across the Spanish ships that Oxenham released, and they were able to give more instructions of where the pirates went, the Gulf of San Miguel. In hot pursuit, Ortega came to a place that 3 rivers merged, and was not sure which branch to take, when he saw a bunch of chicken feathers, drifting down one of the branches. The pirates had already dragged their pinnace on the river bank and covered it up, to hide it from the Spaniards. They left a small guard consisting of 6 men to protect the pinnace, and the rest started across the jungle, heading north with the treasure. On the fourth day, of traveling up steam, the Spaniards discovered where the pinnace was hidden In the battle, they succeeded in killing one of the guards and captured the others. The only thing in the pinnace was provision, the treasures had been carried away by the pirates heading north.

On the trip North, the pirates started arguing with Oxenham, that they wanted the treasure divided before they would cross the Isthmus. The English agreed to bury the treasure, until they could locate some Cimarron's to help carry it back. This squabbling, resulted in the loss of 15 days, allowing sufficient time for Ortega to catch the Pirates.

The Spaniards continued after the pirates, with 80 men, leaving the others to guard the captured pirates. After traveling about half a league in their pursuit, they found a freshly dug mound covered with tree branches. They dug it up, and found all of the treasure that had been captured by Oxenham. Once they had the treasure in hand, they called off the pursuit and decided to returned to Panamá. 

The Cimarron's rushed to where the pirates were hidden and informed Oxenham what had happened. Oxenham, then ordered his men to turn around, and recapture their treasure. They intended to intersect the Spaniards before they reached Panamá, attack them, and take back their booty. They made enough noise, that Ortega, who had not even started his return to Panamá, had time to position his men for an attack. The pirates miscalculated the strength of the Spaniards, and were instead routed. The Spaniards killed 11 of the pirates and captured seven of them. Only 2 Spaniards were killed and a few were wounded. The rest of the pirates retreated and took off, back across the Isthmus.

The captured pirates were tortured, and they reveled the complete plans of the expedition. They also informed where their ships was hidden, and who was helping them. The governor, sent messengers over the Gold Road across the Isthmus to Nombre de Diós, , on horseback. He ordered them to go as fast as possible and stop for nothing. They carried orders, informing the military commander of Nombre de Diós, as to the location of the pirates camp and the hidden ship. The Spanish soldiers soon found the hidden cove at Port Pheasant and the hidden ship which they captured and took back to Nombre de Diós, before the pirates returned.

When the exhausted pirates arrived at their base, they were greeted by the destruction of their supplies and the disappearance of their ship. Again, the Cimarron's came to their rescue, and supplied them with food and tools, to build another pinnace. Unfortunately for the pirates, they were hit with a bout of Chagres Fever, and the majority of them died, with the exception of 18 men. While they were convalescing under the cared for of the Cimarron's, the Spaniards returned. By orders of the viceroy of Peru, a large force of 150 men returned to capture the pirates. They were able to surprise all of the pirates, and captured them. All 18 of the surviving Englishmen and 40 Cimarron's were transported to Panamá in chains.

When they arrived in Panamá in April, 1578, the Englishmen were tried for piracy,  convicted and sentenced to death. Oxenham took full responsibility for the expedition and denied that he had a letter from the English government, authorizing him as a privateer.

The 10 surviving adults were hanged in the main city plaza, while the 5 cabin boys turned over to the governor to serve as servants. The Cimarron's were sold back into slaver, while Oxenham, Butler and Thomas Sherwell, the officers of the expedition, were taken to Lima, Peru and executed late in 1580. 

This expedition had many firsts. They were the English to sail the South Sea, the first English to capture treasure ships in the South Sea, the first English pirates to be captured and executed in Tierra Firme.