In the opening sequence, we see Claire Redfield riding into Raccoon City on her motorcycle. Claire, who is the younger sister of Chris Redfield (one of the S.T.A.R.S. members who survived the mansion incident), has traveled to Raccoon City to find her brother. Upon her arrival, Claire notices that the city is unusually desolate. She arrives at "Emmy's Diner", which appears to be empty as well, but she soon learns differently, when she is suddenly approached by a Zombie. Horrified, Claire attempts to flee the diner, but finding her escape route blocked by the walking dead, she makes a break for the emergency exit. On the other side of the door, she is met by Leon S. Kennedy, another survivor, who aims his gun at her, Claire pleads with him to not shoot, but he tells her to duck so he can dispose of the zombie behind her.

Rookie police officer Leon drives into Raccoon City ready for his first day, soon discovering it besieged by zombies. Joining fellow survivor Claire Redfield, the two drive in a police car to the Raccoon Police Station in the hopes of finding help. Attacked by a zombie from the back seat, they swerve 180 degrees and collide with the back of the station, killing the zombie. A truck then crashes into the car, separating Leon and Claire on different ends of the road. Leon makes his way into Kendo Gun Shop, where he meets the shopkeeper, who warns him that the entire town is infested, before being eviscerated by zombies that break in. Leon flees, and later enters the Raccoon Police Station through its front door and is introduced to his superior, Marvin Branagh, who warns him that the Zombie-related killings have been going on for months, but were ignored completely, until two months earlier, after the S.T.A.R.S. team was discredited.

In a hostile, post-pandemic world, Joel and Ellie, brought together by desperate circumstances, must rely on each other to survive a brutal journey across what remains of the USA.