The action of the prologue takes place 15 years before the main events of the game, as well as before the events of the first part of the series. Nathan Drake (Nolan North) is in the Panamanian prison with his brother Sam (Troy Baker) and accomplice Rafe Adler (Warren Cole). They bribe Vargas’ security chief, Hemki Madera, to allow them to investigate an abandoned cell in a destroyed tower in the prison. In the cell, Nate finds the cross of St. Dismas, in the cavity of which, according to the heroes, there should be a map showing the location of Henry Avery’s treasures, but the cross was broken and the map was missing. Sam offers to continue the search for treasure in Scotland, where St. Dismas’s Cathedral is located and where Avery’s trail is lost. Vargas, learning of the heroes’ plans to search for treasure, demands that they include him in the share, but Rafe kills him and the heroes have to flee. During the escape, the guards open fire on the defeat and hit Sam, after which he falls from the roof of the building. Rafe convinces Nate that his brother is dead and there is nothing to help him. Nate reluctantly agrees, and the two of them escape from prison.

It has been 15 years since then (and three years after Uncharted 3): with a treasure hunt, Nathan Drake works as a diver at the private search and rescue company Jameson Marin in New Orleans and lives a quiet family life with Elena Fisher. (Emily Rose). One morning, Sam, who survived the injury, comes to his office and is sent back to prison for killing Vargas. According to Sam, he was able to be released thanks to drug lord Hector Alcazar (Robin Atkin Downs), with whom he spent the last year in the same cell. After escaping, Alcazar gave Sam three months to search for treasure, threatening to kill him. Sam also found out that in three days in the estate of Rossi in Italy will be an illegal auction, in which one of the lots will be another cross of St. Dismas, this time intact. Nate travels with his brother to Italy, telling Elena that he has agreed to work in Malaysia, for which he was long persuaded by Jameson (Brandon Scott), Nathan’s employer.

The brothers were able to get to the auction with the help of Victor Sullivan (Richard McGonagall), who turned out to be familiar with the organizer of the event. It turns out on the spot that the order of the lots has been changed and the Dismas cross will be displayed in just a few minutes. The heroes decide to commit a sabotage, turning off the electricity, and, taking advantage of the confusion, to steal the cross. However, Rafe intervenes in their plans, who all these years did not stop trying to find Avery’s treasures. Inheriting his father’s company, becoming a very rich and influential man, Rafe hires Nadine Ross (Laura Bailey) and her army from the private military company “Shorline” to search for treasure. After the abduction of the cross, the hunt for the heroes begins, but they manage to leave the estate and escape persecution.