Treasure hunter Nathan "Nate" Drake, joined by reporter Elena Fisher, hauls up the coffin of his self-styled ancestor Sir Francis Drake, having pinpointed it from coordinates engraved on a family heirloom — the ring he wears on a cord around his neck. Inside lies Sir Francis's diary, which points the way to El Dorado. When pirates ambush and destroy Nate's boat, his friend and mentor Victor "Sully" Sullivan swoops in to rescue the pair in his seaplane. Wary that Elena's reporting will draw rival fortune-hunters, Nate and Sully ditch her at a dock.
Following the diary, the two uncover an alcove that once cradled a huge statue and realize El Dorado is no lost city but a golden idol. A nearby Nazi U-boat yields a torn diary page revealing the statue was shipped to an island — but mercenaries under crime lord Gabriel Roman and his lieutenant Atoq Navarro intercept them. Sully is seemingly killed by a shot to the chest, yet Nate escapes, reunites with Elena, and flies with her to the island.
En route, anti-aircraft fire forces the pair to bail out, scattering them. After scavenging supplies from the downed seaplane, Nate makes for an old fort to find Elena, only to be briefly seized by pirates led by his former associate Eddy Raja; Elena frees him and they flee to the island's old customs house. Records there show the statue was moved deeper inland — and that Sully is alive after all, traveling with Roman and Raja. Nate and Elena track him down and rescue him, learning that Drake's diary had stopped the bullet and that Sully had been feeding Roman false information to buy Nate time.