Ten-year-old Nathan Drake and his five year older brother Sam live in an orphanage in Boston after the death of their parents. One night, they try to steal the first map made after the Magellan expedition, but they are caught by the museum's security. Because this is Sam’s third strike, the orphanage kicks Sam out and he shall be brought elsewhere, away from Nate. Nate goes to their room and catches Sam sneaking out to be on his own, but he promises his little brother that he will return for him. Sam leaves him with a ring belonging to their ancestor Sir Francis Drake, with the inscription “Sic Parvis Magna” (“Greatness from small beginnings”).
Fifteen years later, Nathan works as a bartender and pickpockets wealthy patrons. Victor "Sully" Sullivan, a fortune hunter who worked with Sam tracking treasure hidden by the Magellan crew, explains to Nathan that Sam vanished and ghosted him after helping him to steal Juan Sebastian Elcano's diary. Nathan, who has several postcards Sam sent him over the years, agrees to help Sully to find his brother. Sully and Nathan, disguised as auction attendants, go to an auction to steal a golden key (in the shape of a cross) linked to the Magellan crew. There, the pair encounter Santiago Moncada, the last descendant of the Moncada family (who funded the original expedition), and Jo Braddock, leader of mercenaries hired by Moncada. Nathan is ambushed by Braddock's men, and the ensuing fight creates a distraction for Sully to steal the key.
The duo travel to Barcelona, where the treasure is supposedly hidden, and rendezvous with Sully's contact Chloe Frazer, who has the second key. Chloe steals the first key from Nathan, but Nathan and Sully convince her to work with them. Meanwhile, Moncada confronts his father, Armando, upon learning the family fortune is being donated; after Armando states that his son is not worthy of inheriting it, Moncada orders Braddock to kill him. Nathan, Chloe, and Sully follow clues in Elcano's diary to Santa Maria del Pi, finding a secret crypt behind the altar. Nathan and Chloe enter, finding a trap door, but as they open it, the crypt floods with water. Sully barely manages to help them escape after subduing an ambush by Braddock. Using the two keys to unlock a secret passage, Nathan and Chloe find a map that indicates the treasure is in the Philippines. Chloe betrays Nathan (having originally been hired by Moncada) and takes the map.
Sully reunites with Nathan and says after he and Sam recovered Elcano's diary, they were ambushed by Braddock; Sam was shot, and Sully narrowly escaped. Moncada is betrayed and killed by Braddock, who departs in a cargo plane to find the treasure; Nathan and Sully hide on the plane. Nathan confronts Braddock while Sully parachutes out. Nathan is knocked out the plane with Chloe (who attempts to escape with the map after Moncada's death) and the pair land in the Philippines, where they realize the map does not pinpoint the treasure. After surmising Sam may have left a clue in his postcards, Nathan concludes the treasure's location. Unsure over Chloe's loyalties, Nathan leaves her fake coordinates and reunites with Sully, finding the Magellan ships. Braddock follows them, forcing Nathan and Sully to hide as her crew airlift the ships.
During their escape, Sully commandeers one of the helicopters, causing Braddock to order the other helicopter to approach for a boarding action. Nathan defends himself from her mercenaries and shoots down the other helicopter with one of the ship's cannons. Braddock drops the ship's anchor while Nathan climbs up to the helicopter. Sully throws a bag of collected treasure at Braddock, who is crushed to death when the ship breaks and falls. As Philippine naval units arrive, Nathan and Sully escape with a few pieces of pickpocketed treasure, while Chloe (who followed them by boat) is left empty handed. In a mid-credits scene, it shows that Nate's lost brother, Sam, is alive but is being held in prison, where he is writing another postcard to his brother.
- Tom Holland as Nathan Drake, a young fortune hunter and bartender, in whom Sully recruits to find the fabled treasure of the Magellan expedition and claims to be a descendant of famed English explorer, Sir Francis Drake.
- Tiernan Jones as young Nathan
- Mark Wahlberg as Victor "Sully" Sullivan, a seasoned fortune hunter, who previously worked with Nathan's brother, Sam. Wahlberg was originally set to star as Drake in the film's early development.
- Antonio Banderas as Santiago Moncada, a ruthless treasure hunter, who is a lone descendant of the Moncada family.
- Sophia Ali as Chloe Frazer, a fellow fortune hunter, an associate of Sully's, and Nate's frenemy turned romantic interest. Frazer was previously portrayed by Claudia Black, through both voice and motion capture, appearing in Among Thieves and Drake's Deception, and being the main protagonist in The Lost Legacy, with Black reprising her role, by voice-portrayal and Michelle Lee doing the motion capture portrayal for the character.
- Tati Gabrielle as Jo Braddock, a mercenary who works for Santiago Moncada, against Nate and Sully.
- Rudy Pankow as young Samuel "Sam" Drake, Nate's long-lost brother.
- Manuel de Blas as Armando Moncada, Santiago Moncada's father.
- Steven Waddington as the Scotsman, a henchman with a very Scottish accent, who works for Braddock.
- Alana Boden as Zoe.
- Pingi Moli as Hugo.
- Nolan North as a tourist on the beach, in the Philippines. North previously portrayed Nathan Drake in all four Uncharted games: Drake's Fortune, Among Thieves, Drake's Deception and A Thief's End.
- Pilou Asbæk as Gage.
The soundtrack contains most of the music that is featured in the film. It was composed by Ramin Djawadi and released on February 18, 2022 with 23 tracks. Djawadi also composed a reprisal of "Nate's Theme" by Greg Edmonson, from Uncharted: Drake's Fortune, Uncharted 2: Among Thieves, and Uncharted 3: Drake's Deception in the film. Additionally, American band, MILKBLOOD, produced an original song, titled "No Mind", released on February 16th, 2022, just a couple days prior to the film's release, and was used for the end credits sequence.
|5||I'm All In||3:04|
|7||Only One Rule In This Game||2:28|
|8||Heart of Gold||4:59|
|11||Skeleton with Angel Wings||3:12|
|12||Give Me The Cross||6:26|
|15||Ready To Make History||1:49|
|16||Have Some Respect||2:13|
|17||House of Moncada||1:49|
|19||A Whole World You Haven't Seen||1:40|
|22||Lost Not Gone||5:28|
|23||The Biggest Treasure Never Found||4:12|
- Four characters of the games appear in the movie: Nathan Drake, Samuel Drake, Victor Sullivan, and Chloe Frazer.
- Another two characters of the movie are similar to characters appearing in the games:
- Nolan North who voiced and performed motion capture for Nathan Drake in the games of the Uncharted series, has a cameo in the film as a tourist in the Philippines. When Nate and Chloe wash up there after falling from the plane, he asks what happened to them. Nate answers to him, "Fell out of a car that fell out of a plane." The tourist replies, "Huh. Hey, you know, something like that happened to me once.", referring to the plane fight scene from the 17th chapter of the video game, Uncharted 3: Drake's Deception: "Stowaway". A soft reprisal of the Uncharted games' theme music accompanies North's cameo, as a fun bonus.
- The movie has numeral allusions to events, objects, and locations of the games.
- The most similar scenes are the auction of the cross (cf. A Thief's End - Once a Thief...) and Nate falling out of an airplane (cf. Drake's Deception - Stowaway).
- Among the objects from the games appearing in the movie are Francis Drake's ring and Sam's lighter. Further, the fact that two crosses are required for finding the treasure alludes to thw two Saint Dismas Crosses from A Thief's End
- The most similar location is the cave in which a treasure ship is hidden.
- Brian Crecente: The Man Behind Marvel Movie Magic Hopes To Do the Same For Gaming, October 2, 2008.