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Claire Redfield arrives Raccoon City in search of her brother, making her way to the Raccoon City Police Department. In the main lobby, she is confronted by a group of zombies, which are quickly dispatched by Leon S. Kennedy as he also arrives. Meeting each other, the two agree to inspect the station. In the process, they happen upon Sherry Birkin, who runs away shortly after she sees them. They also meet the surviving chief of police, Brian Irons.

After Irons is killed by a G-Young erupting from his chest, Leon and Claire fight it and the mutant William Birkin. They then enter the sewers, operating two doors simultaneously in order to open a route to a tram. When this is performed, Claire heads back to the police station looking for Sherry. Finding her in an upstairs room, Sherry quickly runs away again, adamant she must find her father. Going around the sewers looking for her, Claire meets Sherry's mother, Annette Birkin and learns about the G-Virus William injected himself with. The two women hear a scream and Annette conscripts Claire into protecting her daughter.

Returning to the police station, Claire finds Sherry in a bathroom. She is told that Sherry's stomach hurts and that she has met her father, understanding his transformation. Claire takes Sherry to the sewer tram, which they and Leon use to get to a laboratory. Placing Sherry in a safe room, Leon and Clear search the facility for a vaccine to treat the girl. They eventually succeed in creating the base vaccine when Claire stumbles onto Annette again, who shows she has a sample of the G-Virus with her. Claire reveals Sherry's condition, but Annette can do little about it when William arrives and seriously injures her before leaving. A dying Annette tells Claire about the vaccine and hands her a file on the production of the vaccine, along with the "G" sample.

With the base vaccine and the "G" sample, Claire is able to create the vaccine and administer it to Sherry as they return to the tram, now able to travel to the city limits. Just when they think it's finally over, Leon gets locked into another tram car while the mutated William attacks. Once William is dispatched, Leon; Claire, and Sherry leave the tram and the game ends with Claire still searching for her brother.