In a flashback, Claire and Chris Redfield are children that are living in the Raccoon City Orphanage. Claire meets and befriends Lisa Trevor, a disfigured girl who has been experimented on. Dr. William Birkin, an employee for the Umbrella Corporation, oversees the orphanage and takes children for his own experimental research. Later, Birkin takes Claire to experiment on her, who escapes.In 1998, Claire returns to Raccoon City, hitchhiking in a semi-truck. While distracted, the truck driver hits a woman who is walking in the road. When Claire and the driver investigate, the woman disappears, leaving only a pool of blood behind. The truck driver's Dobermann licks the blood, and over time begins to foam at the mouth and becomes erratic. Meanwhile, Leon S. Kennedy, a rookie police officer, wakes up for his first day with the Raccoon City Police Department. He goes to the town's diner where he falls asleep at the counter. Jill Valentine and Albert Wesker, who are also at the diner, wake Leon up as they leave. Leon notices that the diner's owner has blood coming from her eyes when a deformed crow crashes into the window.Claire heads to Chris's home where she picks the lock with her knife and enters. Chris comes downstairs en route to the police station and Claire explains that she returned to Raccoon City to warn Chris about the Umbrella Corporation. She explains that she has contacted conspiracy theorist Ben Bertolucci, who claims that Umbrella has erroneously poisoned the city's water. Meanwhile, a siren goes off informing citizens to stay in their homes. Chris leaves for the police station while Claire steals his motorbike. Before Claire leaves a child breaks into the house, running from his mother; both have severe hair loss, are erratic, and bloody.At the police station, the STARS Alpha team meet with Chief Brian Irons to discuss the recent events. Irons explains he doesn't know what is going on, but that Bravo team is missing while investigating a death at the Spencer Mansion. Alpha team is sent to the mansion to see what has happened. At the meeting, an unknown person pages Wesker to check his locker, which contains a PDA with instructions on it. Traveling in a helicopter, STARS team find bravo team's police car and follow tracks to the mansion. Inside, the team splits up with Wesker and Jill going upstairs. There, Wesker secretly follows the map on his PDA and enters a secret code on a piano, revealing a secret passage. Jill then sees their helicopter crashing into the mansion, after pilot Brad Vickers gets bitten by a zombie. Afterwards, Wesker reveals that he has been hired to reveal secrets of Umbrella, and will use the secret passage to steal Dr. Birkin's virus. Wesker saves Jill from a zombie before leaving the team. Meanwhile, Chris and Richard Aiken encounter zombies eating the bodies of Bravo team. Richard is eaten while Chris battles the horde, with Jill ultimately saving him. The pair flee the zombies, following Wesker into the secret passage.Leon is asleep at the front desk of the police station when the truck driver, now bitten by his dog, begins to turn into a zombie and crashes his truck at the entrance of the station. Chief Irons shoots the aflame zombie, awakening Leon, then announces he is leaving, putting Leon in charge. Irons travels out of the city, but is stopped by Umbrella guards who shoot civilians who are trying to escape the city. Returning to the station, Irons is attacked by a zombie dog but Claire rescues him. Claire and Leon go down to the armory to secure supplies when Leon encounters Ben Bertolucci, who is imprisoned. Ben steals Leon's gun, but a zombie inmate bites him before he is able to escape his cell. Leon, Claire, and Irons then abandon the police station and travel to the Orphanage, looking for a secret Umbrella tunnel in the building. While there they encounter a licker which kills Irons and attacks Leon, but he is saved by Lisa who recognizes Claire and gives them the keys to the secret passage.Wesker, traveling through the passage, encounters Dr. Birkin who is in the midst of securing his life's work. Birkin reaches for his gun shooting Wesker in the chest before Wesker shoots Birkin, nearly killing him. Birkin's wife Annette then grabs the gun, but Wesker shoots her as well. Then, Birkin's daughter Sherry grabs the gun. Wesker hesitates to pull the trigger, before being shot by Jill. Chris rushes to Sherry and finds that William has injected himself with the G-Virus. Chris and Jill run from Birkin, who begins to mutate. Claire and Leon then shoot Birkin, letting the five survivors escape to an underground train. The train is stopped when Raccoon City begins to be destroyed, allowing a fully mutated Birkin to attack the train. Leon shoots him with a rocket launcher, killing him.In a mid-credits scene, Wesker awakens in a body bag, unable to see anything. A figure then hands him sunglasses and reveals herself as Ada Wong.