The film begins with Nathan Drake (Tom Holland) hanging in front of a plane and becoming tangled in fallen cargo. He attempts to climb back up, dodging henchmen and more falling cargo. Just as he makes it back upstairs, he is hit by a car falling off the ramp. As Nate falls, a hand grabs him.
Cut to a flashback 15 years ago in Boston. Nate (played here by Tiernan Jones) and his older brother Sam (Rudy Pankow) break into a museum to steal the original map of Ferdinand Magellan's expedition, as legend has it that Magellan's entire journey was to find hidden gold. The brothers are caught by security guards, and since this is Sam's third strike, the orphanage that is housing both boys kicks Sam out, forcing him to stay somewhere else, away from Nate. Nate goes to her room and catches Sam sneaking out to be alone, but he promises his little brother that he will come back for him. Sam leaves him a ring belonging to her ancestor, Francis Drake, with the inscription "Sic Parvis Magna" ("greatness from small beginnings").
Present – Nate works as a bartender. He waits on a snooty rich girl and takes the opportunity to steal her bracelet if she doesn't notice. Nate is being watched by a fortune hunter named Victor "Sully" Sullivan (Mark Wahlberg). He offers Nate a chance to work together, but Nate declines. He soon finds out that Sully stole his bracelet and left him his business card.
Nate goes to Sully's office to get the bracelet back, but then stumbles upon other artifacts in Sully's possession, including the same card he and Sam were trying to take. Sully reveals that he used to work with Sam and knew Nate was his brother. They discuss Magellan's journey and how it was funded by the Moncada family, who have been responsible for various atrocities throughout history. Sam had helped Sully steal Juan Sebastian Elcano's journal with clues that could lead them to Magellan's fortune. Nate is initially unwilling to help Sully finish the work he and Sam have started, but Nate looks at the postcards Sam has sent him over the years and soon changes his mind and calls Sully .
Sully informs Nate that they must acquire a gold cross, which is one of two keys to finding Magellan's gold. He has the first, the second is being auctioned off in a museum. Sully knows that Santiago Moncada (Antonio Banderas) will try to buy the cross, believing it is his birthright. The duo prepare for their heist, with Nate checking up on some background information about Sully to know who he's working with.
The two go to the auction where Sully is unsettled to see a woman named Jo Braddock (Tati Gabrielle) there. He knows her as a mercenary and has had run-ins with her in the past. Braddock approaches Sully and indicates that she knows he is there for the cross as well. Nate tries to turn off the power as the auction begins, but is caught by Moncada's tall, burly Scottish henchman (Steven Waddington). Sully must buy time by trying to outbid Moncada, even though he knows he doesn't have the money to do so. After avoiding the Jock and another thug, Nate eventually creates a distraction by dangling from the chandelier, causing a commotion. Sully grabs the cross and sets off, but is almost intercepted by Braddock until other guards show up, and she violently deals with them. Nate escapes the other security guards and gets in Sully's car to drive off together.
Nate and Sully take the cross and travel to Barcelona to meet up with Sully's associate Chloe Frazer (Sophia Ali), who is in possession of the second cross. She doesn't trust Nate to be there with Sully, but she proves her own unreliability shortly thereafter by stealing the cross from Nate's pocket. Nate and Sully give chase to Chloe, but even though she almost escapes, Nate reminds her that she doesn't really know where to find the treasure without her help. Based on clues Nate studied in the journal, he determines that they must start by going to a church, Santa Maria del Pi. While staying in a hotel room for the night, Chloe brings up something that Sully doesn't tell Nate about Sam.
At the Moncada Foundation headquarters, Moncada is upset to learn that his father, Armando (Manuel de Blas), is donating the family fortune. He tells Santiago that he is not worthy of inheriting it. After one last chat with his father, Moncada has Braddock kill Armando before taking the money to set off on his own expedition.
Nate, Sully and Chloe go to the church and find the underground secret passage. Using the crosses, they attempt to open an entrance, but they accidentally set off a booby trap due to Sully misreading the instructions in the journal. Nate and Chloe go through the entrance with one key while leaving the other with Sully. Down there, Chloe says she distrusts people because her own father ran off with money from a discovery she made and left his family. They end up in a nightclub, the next course of which is hidden behind the bar. The jock and another of Braddock's idiots find her while Braddock himself is in pursuit of Sully. Nate and Chloe manage to create a distraction and fend off the Jock before heading through the entrance.
Nate and Chloe come across a trap door and try to unlock it with their cross. The room then begins to fill with water, requiring Sully to use the other cross to get her out. He is ambushed by Braddock when he finds out the other keyhole is behind glass in a restaurant wall. Sully fights Braddock and throws her against the glass to break it open and free Nate and Chloe before they drown. Once clear, the two will find another room that requires both crosses to unlock the door. Sully throws down his cross, and Nate and Chloe find giant urns that they believe contain the gold. Instead they are all filled with salt and shatter. Nate finds a map hidden in the salt that indicates the treasure is in the Philippines. Unfortunately, Chloe takes this opportunity to trick Nate and take the card for herself. She tells Nate that Sully is hiding the truth about Sam from him before pistol whipping and knocking him out.
Sully finds Nate, but when he wakes up, he asks Sully what happened to Sam. Sully admits that he and Sam were ambushed by Braddock who shot Sam and Sully had no choice but to run and leave him behind, leading her to believe Braddock killed Sam. Nate angrily walks away from Sully.
Sully finds Nate, but when he wakes up, he asks Sully what happened to Sam. Sully admits that he and Sam were ambushed by Braddock who shot Sam and Sully had no choice but to run and leave him behind, leading her to believe Braddock killed Sam. Nate angrily walks away from Sully.
Braddock meets up with Moncada, who reveals he has hired Chloe as part of his team, and she brings him the map. He is making preparations to travel to the Philippines with his crew. Nate and Sully reconcile and plan to stow away on the plane by hiding in the trunk of Moncada's car. On the plane, Moncada gathers his crew and talks about how he feels that Magellan's crew betrayed his family and that the gold they were supposed to find belonged to the Moncadas. Braddock then betrays Moncada and cuts his throat in front of the crew, then takes responsibility for them. Nate and Sully sneak out, but Nate's pride overwhelms him and he makes his presence felt to confront Braddock about shooting Sam. He has the cargo chutes open, leading Sully to use his own chute to fly out of the plane while the henchmen are thrown out of the plane. Chloe gets in the car with the card, which KOs Nate, and the two manage to parachute onto a cargo and end up in the sea. They float until they reach an island resort.
Nate and Chloe take a room and try to scan the map, but they find they can't find the exact location of the treasure. While Chloe sleeps, Nate uses one of Sam's postcards and lights a flame underneath to reveal a hidden message that says, "The keys are your compass." Nate uses the crosses and finds the exact location on the map. He writes down wrong coordinates, knowing that Chloe will see them and run away. She does, and Nate pulls out the correct coordinates.
Nate uses a speedboat to go to the location when Braddock and her thugs also arrive. Sully finds Nate coming over the cave with two ships intact. The gold is also in the ships. Just as Nate and Sully are getting their hands on the treasure, Braddock has the ships evacuated from the caves, as the ships themselves are worth billions. Sully climbs onto one of the helicopters and knocks down Braddock's goon. She notices him in the other helicopter and her men begin to attack. Nate and Sully fight the men on the ship and push them into the ocean. The Scot ends up crashing his helicopter and one of the ships on the side of a huge rock. Braddock tries to track Nate and kill him himself. When Nate tries to climb to the helicopter, Sully must choose between saving him or the gold. Sully throws the bag of gold at Braddock and drops them in the ocean. He pulls Nate up and the second ship falls straight onto Braddock, crushing them.
Nate and Sully fly away, with Nate revealing he saved some gold. They look down and sneer at Chloe on her speedboat, knowing she's been tricked. The two then fly together on their next adventure.
Before the credits: We cut to a prison where we see that Sam is still alive and is writing another postcard to Nate.
Mid-credits: Nate meets up with a man named Gage (Pilou Absaek) to purchase an item for a man named Roman (who is setting up the events of the first video game). Sully also sports a mustache, which Nate makes fun of. Just as the boys think they are about to flee, they are ambushed by gunmen.
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