The Last of Us is a third-person action-adventure game, set in a post-apocalyptic world where a deadly parasitic fungus (Cordyceps unilateralis) that infects the brains of ants suddenly adapts to humans. A large portion of the human race turns into monster, called the infected or clickers. The remaining survivors turn to whatever assets they can find to survive a world now overrun by anarchy and desolation.

The player takes the role of Joel (voiced by Troy Baker) and, with the help of 14-year-old orphan girl Ellie (voiced by Ashley Johnson), must try to survive at all costs, fending off both the infected and other desperate human survivors. Supplies and ammunition are scarce and the player will have to constantly evaluate the risk of searching for these supplies in the environment and risking unwanted and taxing confrontations.