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.

After a harrowing trek across a desolate United States, Joel and Ellie find themselves navigating a dangerous Kansas City on foot. Later, rebel leader Kathleen instigates a manhunt – one that pits her violent civilian militia against the world's best hope.

As Joel fights to survive, Ellie’s struggle to save him stirs memories of her life in a FEDRA orphanage. Weeks before meeting Joel, Ellie recalls joining her best friend Riley for a night to remember… one that will change the course of both of their lives – and the fate of the world – forever.