Several years before the events of the first game, Nate and Sam hunt for the treasure of pirate Henry Avery, who plundered a fortune during the 1695 Gunsway heist. Alongside Rafe, the Drake brothers infiltrate a Panamanian jail to access the former cell of Avery's first mate, where Nate discovers a hollow St. Dismas idol. When the prison warden who aided them demands a cut, Rafe impulsively kills him, triggering a frantic escape. Nate and Rafe successfully escape, but Sam is shot by guards, presumed dead.

Fifteen years later, following the events of the previous game, Nate has retired with his wife Elena but misses the excitement of his old life. He is visited by Sam, who survived the gunshots and has spent the intervening time incarcerated. He explains that he escaped with drug lord Hector Alcazar, who demands that Sam find Avery's treasure or be killed. Nate agrees to help Sam, lying to Elena that he has accepted a salvaging job in Malaysia which he had actually refused. Aided by Sully, the Drakes steal a duplicate Dismas idol from an illegal auction in Italy, bringing them into conflict with South African mercenary boss Nadine Ross and her employer, Rafe, who is still searching for Avery's treasure. A map inside the idol leads the Drakes to St. Dismas' cathedral in the Scottish Highlands. There, they discover a hidden temple and a map highlighting King's Bay in Madagascar.