Nathan "Nate" Drake is a clever young bartender with a knack for historical trivia and a personal connection to the legendary explorer Sir Francis Drake. He's recruited by seasoned treasure hunter Victor "Sully" Sullivan, who seeks Nate's expertise to decode the mystery behind a never-found 500-year-old fortune amassed by the Magellan expedition and lost by the House of Moncada. Nate, influenced by the disappearance of his older brother Sam, who was also on the trail of the same treasure, decides to join Sully. The duo sets off on a globe-trotting adventure that promises rich rewards and a chance to possibly uncover clues to Sam's whereabouts.

As Nate and Sully follow the trail, they face fierce competition from the ruthless and wealthy Santiago Moncada, a rightful heir determined to reclaim his family's legacy, and Jo Braddock, the leader of an elite mercenary group working for Moncada. They must also solve complex puzzles and decipher cryptic clues that lead them through treacherous terrain, from auction houses in New York to the cultural tapestry of Barcelona, and into hidden caverns where danger and ancient secrets await. Along the way, the unlikely partners must learn to work together, as their quest requires a blend of each other's street smarts and historical knowledge to stay one step ahead of their dangerous adversaries.