In the heart of Boston, two orphaned brothers, Sam and Nathan “Nate” Drake, find themselves in a precarious situation as they attempt to steal a historic map linked to the legendary Magellan expedition. Just as the orphanage prepares to expel Sam, he makes a daring escape, leaving behind a ring that belonged to their supposed ancestor, Sir Francis Drake, and promising Nate that he will return.
Fast forward fifteen years, and Nate is now a bartender in New York City, living a life filled with pickpocketing wealthy patrons. His mundane existence takes a turn when he meets Victor “Sully” Sullivan, a seasoned fortune hunter who once collaborated with Sam in pursuit of treasure hidden by the Magellan crew. Sully reveals that Sam has gone missing after helping him steal Juan Sebastián Elcano’s diary. Concerned for his brother, Nate decides to join Sully in the quest to find Sam.
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The duo’s first mission leads them to an auction where they plan to steal a golden cross linked to the Magellan crew. Here, they encounter Santiago Moncada, the last descendant of the Moncada family, who financed Magellan’s expedition, and Jo Braddock, the ruthless leader of Moncada’s mercenaries. In a twist of fate, Nate is ambushed by Braddock’s men, but the chaos allows Sully to successfully steal the coveted cross.
With the golden cross in hand, Nate and Sully travel to Barcelona, where they meet Chloe Frazer, Sully’s contact who possesses the other cross. Together, they delve into Elcano’s diary, following clues that lead them to Santa Maria del Pi. Inside a secret crypt behind the altar, they discover a trap door, but their excitement quickly turns to panic as the crypt floods with water. Sully comes to their rescue, subduing Braddock’s ambush and helping them escape.
Using the two crosses, Nate and Chloe unlock a hidden passage that reveals a map indicating the treasure’s location in the Philippines. However, Chloe’s betrayal becomes evident as she takes the map to Moncada, hinting that Sully is hiding secrets about Sam. In a shocking revelation, Sully discloses that Sam was shot and left for dead by Braddock three years ago, straining their partnership and leaving Nate determined to find his brother.
As Moncada, Chloe, and Braddock’s team board a cargo plane to pursue the treasure, Braddock murders Moncada, seizing control of the operation. Nate and Sully manage to sneak onto the plane, leading to a fierce confrontation with Braddock. In the chaos, Sully parachutes out with the map, while Nate and Chloe are ejected from the plane, landing in the Philippines, only to discover that the map does not lead to the treasure.
Determined to uncover the treasure’s true location, Nate deciphers hints left by Sam’s postcards. He cleverly leaves false coordinates for Chloe, suspecting her loyalty. Eventually, Nate discovers the long-lost Magellan ships and reunites with Sully, who has followed him. However, Braddock is hot on their trail, forcing them to hide as her crew attempts to airlift the ships.
In a daring escape, Sully commandeers one of the helicopters, while Braddock orders another helicopter to approach for a boarding action. Nate bravely defends himself against her mercenaries, using one of the ship’s cannons to shoot down the approaching helicopter. As Braddock corners Nate, Sully throws a bag of collected treasure at her, sending her tumbling into the sea, where she meets her demise when the ship falls on her.
As the Philippine Navy arrives on the scene, Nate and Sully manage to escape with a few pieces of treasure that Nate had pocketed, while Chloe is left empty-handed. In a surprising twist, it is revealed that Sam is alive, having survived the gunshot wound inflicted by Braddock. He writes another postcard to Nate, urging him to watch his back.