Joel confesses to his brother, Tommy, his responsibility in preventing the Fireflies attempting to develop a cure for the Cordyceps fungus pandemic by saving Ellie from an operation that would have killed her. Four years later, Joel and Ellie have built a life in Jackson, Wyoming, though their relationship has become strained. While on patrol, Joel and Tommy rescue a stranger, Abby, from an Infected horde. They return to an outpost used as a temporary hideout by Abby's group, former Fireflies now part of the Washington Liberation Front (WLF), a militia group based in Seattle, Washington. The group attack Joel and Tommy; Abby seeks revenge against Joel for murdering her father, the Firefly surgeon who was to perform the operation on Ellie. Meanwhile, Ellie and her girlfriend, Dina, search for the brothers. Ellie enters the WLF outpost and witnesses Abby beat Joel to death. Abby spares Ellie and Tommy, who swear revenge.
The player traverses post-apocalyptic environments such as buildings and forests to advance the story. The player can use firearms, improvised weapons, and stealth to defend against hostile humans and cannibalistic creatures infected by a mutated strain of the Cordyceps fungus. Control intermittently switches between Ellie and Abby; the player also briefly controls Joel in the opening sequence. The nimble nature of the player character introduces platforming elements, allowing the player to jump and climb to traverse environments and gain advantages during combat. The player can break glass objects such as windows to access certain areas or obtain supplies. Some areas are navigated by horse or boat.