As the game opens, treasure hunter Nathan "Nate" Drake, accompanied by reporter Elena Fisher, recovers the coffin of his self-proclaimed ancestor Sir Francis Drake, which he located from coordinates inscribed on a family heirloom: a ring Nate wears around his neck.The coffin contains Sir Francis Drake's diary, which gives the location of El Dorado. Pirates attack and destroy Nate's boat, but Nate's friend and mentor Victor "Sully" Sullivan rescues the two.
When Sully and Nate follow the diary to the indicated spot, they discover an empty pedestal meant to hold a statue, and realize that El Dorado is not a city that the Spanish had tried to remove from the island centuries ago, but rather a large golden idol, weighing nearly 500 pounds and likely worth millions.After finding a Nazi U-boat, mercenaries led by criminal Gabriel Roman and his lieutenant Atoq Navarro intercept Nate and Sully. Sully is seemingly killed by a shot to the chest, but Nate manages to escape to an island where Sir Francis Drake's diary claims the idol is located.On the way to the island, anti-aircraft fire forces Elena and Nate to bail out of the airplane and they are separated. After retrieving supplies from Sully's destroyed plane, Nate heads toward an old Spanish fort to find Elena. Briefly captured by pirates led by old associate Eddy Raja, Elena breaks Nate free and they flee to the old customs house on the island. After finding old records showing the statue was moved further inland, they find that Sully has in fact survived his gunshot wound, and is buying time for Nate by giving Navarro misinformation. Nate discovers that the idol is located near the customs house, and finds and rescues Sully, whose survival is due to Drake's old diary blocking the bullet.
Searching through the tunnels of an old monastery, Nate overhears an argument between Roman, Navarro and Eddy, which reveals that Roman hired Eddy to capture Nate and keep the island secure, with the reward being a share of the gold of El Dorado. After Nate's escape, Roman doubts Eddy's ability to do his job further and ignores his superstitious claim that something cursed on the island is killing his men, leading him to dismiss Eddy and his crew.
Nate and Elena find a passage leading to a large treasure vault, in which they find the body of Drake, assuming that he died on the island searching for the treasure. Before they move on, they encounter Eddy and the last of his crew running for their lives, being killed by mutated humans possessing incredible speed and strength. Soon afterwards, Eddy is killed when one drags him into a pit. Nate and Elena escape and find themselves in an abandoned German bunker. Venturing into the base, he discovers that the Germans had sought the statue during World War II, but like the Spaniards before them, learned that the statue was cursed, which caused them to become mutants. Sir Francis, knowing of the statue's power, was actually trying to keep it on the island, by destroying the ships and flooding the city, before he too was killed by the mutants.
Nate attempts to stop Roman from removing the idol from the island, but find that they have discovered it along with capturing Elena. Navarro, knowing of the curse, tricks Roman into opening the statue, revealing that it's actually a sarcophagus containing a mummy infected with an airborne mutagenic virus. Upon Roman turning into one of the mutants, Navarro swiftly kills him and takes control of his men, planning to sell the virus as a biological weapon.Nate then jumps onto the statue and rides it as it is airlifted onto a boat in the bay. There, Nate defeats Navarro and manages to sink both the idol and him to the bottom of the ocean.Sully arrives and Elena and Nate leave the island with several chests of treasure, after displaying affection towards each other
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