A Thief's End continues the story several years after Nathan's last adventure and 15 years after his brother's death. Nathan Drake, once a treasure hunter, is now retired, living a quiet life and married to Elena, a girl he met on one of his adventures. Trying hard to stay off course of anything that would pull him back into the world of danger and adventure, he yields after his brother, whom he thought was dead, appears in his office and asks him for help.

The story centers around the search for yet another hidden treasure, a 400 million dollar worth of treasure, which Nate and Sam tried to find in their younger days but leads they had just didn't pan out. This time, they need to get back on the trail of the treasure as Sam's life depends on it. All the while competing to the same goal with their ex-partner, Rafe, who teamed up with Nadine Ross, the leader of a mercenary outfit known as Shoreline.

The gameplay style and chapter-based singleplayer story presentation follows the path of its predecessors, with some additional features such as a grappling hook which allows Nathan to climb, rappel, or swing across a chasm, and even combine that to take out enemy soldiers. Any tall grass can be used to hide and take out nearby mercenaries in a stealthy manner. During cutscenes, Nate is sometimes given an option how to reply which does not affect the overall story but changes the conversation path or the outcome of a given scene. In this game, a big emphasis is given to vehicles such as boats or cars, which can be driven around and even used to take out enemies blocking your way or pursuing you. During regular cover based combat, you can now mark enemy combatants to remain visible even when behind cover.

After beating the game, there are lots of unlockables on which the player can spend earned points, from various artwork to new character outfits and different video modes. For example, the entire game can be played in a cel shaded graphic style.