The story is set two decades after a cordyceps-type fungus has killed millions, with nature gradually retaking the abandoned cities and towns. The survivors are hemmed inside quarantine zones, completely under the heel of the United States military, with order and screening for any Infected being viciously maintained under martial law. Joel, a hardened black-marketeer within one of the quarantine zones, goes through an event which makes him promise an old friend that he will get a young, fourteen year old girl named Ellie, away from the harsh regime to a resistance group known as the Fireflies. They begin a journey through the U.S., avoiding the Infected, humanoid creatures whose sole aim has become spreading the fungal infection. Joel and Ellie also have to avoid scavengers that survive outside the quarantine zones who see Joel and Ellie as their latest prey. Adding to their problems, the military is determined to find Ellie and bring her back under their power.