Claire Redfield rides into Raccoon City on her motorbike looking for her brother Chris. Meanwhile, a man at a gas station is getting in a gas tanker complaining about being bitten. When Claire searches a restaurant, she is approached by a zombie. Heading for the back door, she opens it, seeing rookie R.P.D officer Leon S. Kennedy telling her to "Get down", before he shoots the Zombie in the head, killing it instantly. He then suggest they head to the police station, as it will be safer.
They run past the zombies that Leon was apparently fighting, and get in a police car. After introductions are made, Leon tells Claire to open the glove compartment, giving Claire a handgun. Suddenly, a zombie appears from the back seat, causing Leon to go on the road in front of the gas tanker, then crashing backwards into a lamp post. When the two see the incoming out-of-control tanker, they get out of the car just in time to escape the impact of a fuel truck with the car, unfortunately with them both getting out on different sides, and the burning fuel tanker blocking the way to each other.
As Claire makes her way to the Raccoon Police Station's helipad, she bears witness to a helicopter coming to the rescue of a police officer. As he is shooting his sub-machine gun at some zombies, he gets grabbed from the back and aims up while holding the trigger, accidentally shooting the pilot, who goes out of control and crashes into the side of the complex.
Claire then finds the S.T.A.R.S. Office, where she encounters Leon again. He gives her Chris' Diary, and upon reading it, she discovers that Chris traveled to Europe on a lead on Umbrella. He then gives her a radio and suggests splitting up, looking for survivors, then getting out.
Claire later encounters the chief of the R.P.D.; Brian Irons, who tells her the secret to killing a zombie. She then left to find a young girl called Sherry, who runs away after the two hear a monster. After finding certain items, Claire and Sherry find Irons' route down a secret room in his office. There, Claire witnesses Birkin pull Irons down a trap door. Then, it proceeds to tearing Irons to shreds. As Claire approaches the door, the monster throws his horribly mutilated upper torso back up the shaft. She follows Birkin and defeats him.
After his defeat, Claire tries to find Sherry, but finds a dazed Annette, who made her way from the sewers. She accuses Claire of being a spy, but when Claire mentions about Sherry being lost in the sewers, Annette becomes worried about why her daughter did not stay inside the police station. She also gives Claire the shaded answer that Sherry and the G-sample are both in danger. After a short explanation, Annette falls unconscious, leaving Claire confused and worried. When Claire reunites with Sherry, she asks Sherry if she knew about the G-sample, to which Sherry claims that she never knew about it. Once again, Claire asks her once more, but Sherry said she never heard of it. Puzzled with more questions, Claire decides to ignore it for now. The two damsels then descend down into a sewer to find a trolley. The trolley then takes them to a turntable with a vehicle on the rails. After a brief encounter with a persistent T-103, they start descending - Claire having another showdown with Birkin in his third form, with the result being her mortally wounding him.
The turntable stops at an air vent for a Umbrella facility. Claire gives Sherry the vest as a form of friendship, then they exchange emotional words to each other. Claire searches alone when the table starts up again, taking Sherry away. She looks for Sherry again and finds Annette once more. Annette is furious at Claire for losing Sherry, and even threatens Claire with her gun, asking about Sherry's whereabouts, but Claire states that she asked her about the G-sample but she never heard of it, but Annette spots something on one of the camera security monitors - Sherry being attacked by the T-103. Claire asks Annette why the tyrant is after her. Annette directly states that the sample is inside the pendant that Sherry is wearing, so they split up to find her.
They soon reunite when Claire finds Sherry in danger with the T-103, then the tyrant attacks Sherry, but his fist misses her, and she runs off. Claire shouts at Sherry to throw her pendant that has the contained sample to Claire. Claire catches the pendant and tells Sherry to run off to safety. Claire taunts the tyrant with the pendant and throws it into a pool of lava. The tyrant soon falls into the lava, and Claire escapes from the lab to safety, only to find Sherry mourning for her mother, who is on the verge of death. Annette tells Sherry to escape, confesses to her that she loves her daughter very much, and apologises for not being around much. She also asks her to forgive her. Annette dies, leaving Sherry in tears. Claire comforts Sherry and informs her that they must escape. They make their way to a train, then Claire powers up the train when she has another encounter with the T-103. Sometime during the fight, the silhouette of a wounded woman (Ada) throws her a rocket-launcher to finish it off.
She does so, and makes it on the train and starts it when Leon shows up and jumps on the train, but it is not over yet. Birkin does not give up, and mutates into a huge monster, then jumps onto the train. Claire goes to the back of the train and the final battle begins. After defeating it, Leon restarts the train and they make it out before the facility explodes.