2003. As a parasitic fungal outbreak begins to ravage the country and the world, Joel Miller attempts to escape the escalating chaos with his daughter and brother. Twenty years later, a now hardened Joel and his partner Tess fight to survive under a totalitarian regime, while the insurgent Fireflies harbor a teenage girl with a unique gift.

In 2003, an Indonesian scientist makes a devastating discovery. In 2023, now outside of the quarantine zone, Joel and Tess clash over Ellie's fate as they navigate a long-abandoned Boston overrun with Infected.