On a small boat in Panama, reporter Elena Fisher and treasure hunter Nathan Drake retrieve the coffin of famous explorer Sir Frances Drake.
Nate, a self proclaimed descendant of Drake, finds within the journal filled with hand-drawn charts, illustrations and notes by the adventurer himself. According to Nate, "When Drake sailed into the Pacific he took the Spanish fleet completely by surprise. He captured their ships, he took all their maps, their letters, their journals - and he recorded everything in this diary. But when he got back to England, Queen Elizabeth confiscated all of his charts and logbooks," including the one found in his coffin. According to the journal it was the grand treasure of El Dorado that Drake found on his journey. Nate and Victor "Sully" Sullivan quickly set sail for the Amazon, where the journal notes the beginning of their adventure.
After some grand messes and close calls, Nathan eventually finds a projector and document in Drake’s own hand:
"My end is near. The devils hunt for me in the darkness. The gold of El Dorado bears a terrible curse; the Spaniards have unleashed hell, and become as demons. My men have all been murdered, leaving the task to me alone. No ship will depart this island; I destroyed them all, and drowned the cursed city. A thing of such great evil must never leave these shores. In my final hour, I commend my soul to God. May He have mercy on this unholy place."
Turns out that El Dorado, the famed city of gold, is actually a large gold sarcophagus that carries a curse. Making his way toward El Dorado’s new location while being pursued by Gabriel Roman, Atoq Navarro, and their goons - Sully and Nate arrive too late as Roman reveals the horrified mummy inside and unleashes a terrible virus that turns him into the feral creatures Nate has been battling.
Navarro orders the treasure be taken away by helicopter and Nate clings to the net, hitching a ride to a cargo ship. A final showdown with Navarro leads to the statue and Navarro being dragged to the bottom of the ocean floor.