The Last of Us Part II is an action-adventure game set five years after the events of The Last of Us. The player traverses post-apocalyptic environments such as buildings and forests to advance the story. They can use firearms, improvised weapons, and stealth to defend against hostile humans and cannibalistic creatures infected by a mutated strain of the Cordyceps fungus. The game intermittently switches control between Ellie and Abby, and also briefly 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.

Five years after their dangerous journey across the post-pandemic United States, Ellie and Joel have settled down in Jackson, Wyoming. Living amongst a thriving community of survivors has allowed them peace and stability, despite the constant threat of the infected and other, more desperate survivors. When a violent event disrupts that peace, Ellie embarks on a relentless journey to carry out justice and find closure. As she hunts those responsible one by one, she is confronted with the devastating physical and emotional repercussions of her actions.