The Last of Us is an action-adventure game played from a third-person perspective.  The player traverses post-apocalyptic environments such as towns, buildings, forests, and sewers to advance the story. The player can use firearms, improvised weapons, hand-to-hand combat, and stealth to defend against hostile humans and cannibalistic creatures infected by a mutated strain of the Cordyceps fungus. For most of the game, the player takes control of Joel, a man tasked with escorting a young girl, Ellie, across the United States. The player also controls Ellie throughout the game's winter segment and briefly controls Joel's daughter, Sarah, in the opening sequence. 
Listen Mode allows players to discover the position of enemies and characters by displaying their outline through walls, achieved through a heightened sense of hearing and spatial awareness. 
In combat, the player can use long-range weapons, such as a rifle, a shotgun, and a bow, and short-range weapons such as a handgun and a short-barreled shotgun. The player is able to scavenge limited-use melee weapons, such as pipes and baseball bats, and throw bottles and bricks to distract, stun, or attack enemies. The player can upgrade weapons at workbenches using collected items. Equipment such as health kits, shivs, and Molotov cocktails can be found or crafted using collected items. Attributes such as the health meter and crafting speed can be upgraded by collecting pills and medicinal plants. Health can be recharged by finding edible items or through the use of health kits. 
Though the player can attack enemies directly, they can also use stealth to attack undetected or sneak by them. "Listen Mode" allows the player to locate enemies through a heightened sense of hearing and spatial awareness, indicated as outlines visible through walls and objects. In the dynamic cover system, the player can crouch behind obstacles to gain a tactical advantage during combat. The game features periods without combat, often involving conversation between the characters. The player can solve simple puzzles, such as using floating pallets to move Ellie, who is unable to swim, across bodies of water and using ladders or dumpsters to reach higher areas. Story collectibles, such as notes, maps and comics, can be scavenged and viewed in the backpack menu. 
The game features an artificial intelligence system by which hostile human enemies react to combat. If enemies discover the player, they may take cover or call for assistance, and can take advantage of the player when they are distracted, out of ammunition, or in a fight. Player companions, such as Ellie, can assist in combat by throwing objects at threats to stun them, announcing the location of unseen enemies, or using a knife and pistol to attack enemies.