Claire and Chris Redfield are youngsters living in the Raccoon City Convent in a flashback. Claire befriends Lisa Trevor, a deformed teenager who has been subjected to experiments. The orphanage is overseen by Dr. William Birkin, an Umbrella Corporation worker who also takes kids for his own experimental research. Birkin grabs Claire to test on her, but she manages to escape.
Claire comes to Raccoon City in 1998, riding shotgun on a semi-truck. The truck driver strikes a lady who is strolling on the road while preoccupied. The lady vanishes, leaving just a pool of blood left when Claire and the driver investigate. The Dobermann of the truck driver licks the blood and, over time, foams at the mouth and becomes erratic. Meanwhile, rookie police officer Leon S. Kennedy begins his first day on the job with the Raccoon City Police Department.
He goes to a diner in town and falls asleep at the bar. As they depart, Jill Valentine and Albert Wesker, who are also in the diner, wake Leon awake. When a malformed crow crashes through the window, Leon realises the diner's owner has blood streaming from her eyes.
Claire goes to Chris's house and enters by picking the lock with her knife. Claire says that she returned to Raccoon City to tell Chris about the Umbrella Corporation as Chris arrives downstairs en way to the police station. She says she's approached conspiracy theorist Ben Bertolucci, who alleges Umbrella poisoned the city's water inadvertently. Meanwhile, a siren sounds, warning residents to remain in their homes. Claire snatches Chris' motorcycle and drives him to the police station. A youngster breaks into the home before Claire departs, fleeing his mother; both have significant hair loss, are unpredictable, and bleeding.
The STARS Alpha team meets with Chief Brian Irons at the police station to discuss the recent incidents. Irons reveals that he has no idea what's going on, but that the Bravo team has vanished while examining a death at the Spencer Mansion. The Alpha team is dispatched to the estate to investigate the incident.
An anonymous individual asks Wesker to examine his locker, which holds a PDA with directions on it, during the meeting. In a helicopter, the STARS team locates the Bravo team's police car and traces it to the mansion. The squad breaks up inside, with Wesker and Jill heading upstairs. There, Wesker uses his PDA to follow the map and inputs a code word on a piano, which unlocks a secret tunnel. After pilot Brad Vickers is bitten by a zombie, Jill witnesses their helicopter crash into the home.
Wesker then discloses that he has been recruited to divulge Umbrella's secrets, and that he would steal Dr. Birkin's virus through the hidden tunnel. Before departing the squad, Wesker protects Jill from a zombie. Meanwhile, Chris and Richard Aiken come face to face with zombies who are devouring the remains of the Bravo squad. Richard gets devoured as Chris fights the mob, but Jill saves him in the end. Following Wesker through the secret passage, the two evade the undead.
Leon is sleeping at the police station's front desk when the truck driver, who has been bitten by his dog, begins to change into a zombie and smashes his vehicle into the station's entryway. Chief Irons shoots the burning zombie, awakening Leon, before announcing his departure and handing over command to Leon. Irons attempts to leave the city, but is halted by Umbrella guards who murder individuals attempting to flee.
Irons is ambushed by a zombie dog as he returns to the station, but Claire saves him. When Claire and Leon travel down to the armoury to get supplies, Leon runs upon Ben Bertolucci, who is being held captive. Ben grabs Leon's gun, but he is bitten by a zombie inmate before he can leave his cell. After leaving the police station, Leon, Claire, and Irons proceed to the Orphanage in search of a hidden Umbrella tunnel. They come into a licker who kills Irons and threatens Leon, but he is saved by Lisa, who knows Claire and hands them the keys to the secret tunnel.
Dr. Birkin is in the middle of protecting his life's work when Wesker passes through the tunnel. Wesker gets shot in the chest by Birkin as he grabs for his gun. Wesker then shoots Birkin, accidentally killing him. Annette Birkin, Birkin's wife, then takes up the pistol, but Wesker fires her as well.
Sherry Birkin, Birkin's daughter, then takes the pistol. Before even being shot by Jill, Wesker hesitates to draw the gun. When Chris arrives at Sherry, he discovers William has infected himself with the G-Virus. Chris and Jill flee Birkin, who has started to change. After shooting Birkin, Claire and Leon allow the five survivors to flee to an underground train. When Raccoon City is destroyed, the train comes to a halt, allowing a fully transformed Birkin to attack it. Leon kills him by shooting him with a missile launcher.