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 Leon S. Kennedy telling her to "Get Down" and shoots the Zombie in the head, killing it instantly. He then says "Get to the police station, it'll be a lot 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 her gun. Then 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 hitting 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 were she encounters Leon again. He gives her Chris's 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 and looking for survivors then getting out.
Claire later encounters the chief of RPD; Brian Irons, were he tells her the secret to killing a Zombie. She then left to find a young girl Sherry Birkin but then 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 that 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 mortally wounding him.
The turntable stops at an air vent for a Umbrella facility. Claire gives Sherry the vest as a form of friendship, 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, she even threats Claire with her gun, asking about her whereabouts. But Claire stated that she asked her about the G-sample but she never heard of it, but Annette spots something one of the camera security monitors, they spotted Sherry being attacked by the T-103. Claire asks Annette that why the tyrant is after her. Annette directly states that the sample is inside the pendant that Sherry is wearing, they split up to find her.
They soon reunite when Claire finds Sherry in danger with the T-103, the tyrant attacks Sherry but its fist missed her after she ran 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 the hot lava, soon the tyrant falls down into the lava. 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, she confesses to her that she loves her daughter very much and wasn't around much. She also tells 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, 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) throwing 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's not over yet, Birkin doesn't give up and mutates into a huge monster then jumps on 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.