In her attempt to escape a ruined and zombie-infested Raccoon City, Jill Valentine decides she must fight her way out of the city, which had been reduced to complete chaos. Almost being eaten in her initial escape attempt on September 27, she makes her way into a warehouse with Dario Rosso, where they wait it out for another day before she finally gives up on waiting for a rescue party. Dario refuses to leave and locks himself up in a crate.
She stumbles onto fellow S.T.A.R.S. member Brad Vickers by chance, saving him from a zombie attack, although he is bitten. He warns her that they would not make it out, because "he's after S.T.A.R.S. members - there's no escape!"
Jill heads to the police station, searching for any way out of the city. Brad runs to the station after her, warning her to run. He is then killed by the creature he mentioned previously - the Nemesis-T Type.
She escapes two encounters with the monster in the station, and heads downtown to find the source of an emergency radio transmission.
She comes across the source, a mercenary called Carlos Oliveira who worked for Umbrella's "Biohazard Countermeasure Service". Jill initially doesn't trust him, working for the company that caused the disaster in the first place. After helping her survive another encounter with the Nemesis, she begins to trust him. Carlos mentions that there was an escape route set in place as a contingency, in the event that their mission failed. A helicopter is to land near a clock tower once its bell is rung by evacuating mercenaries. To get to the clock tower, Carlos; Sergeant Nikolai Zinoviev and Captain Mikhail Victor (who is injured), plan on using a tram to reach the tower rather than the dangerous roads outside. The tram doesn't work, so Jill and Carlos have to find materials to get the tram working again. Nikolai is apparently lost during their search.
Once the materials are collected, they proceed on the tram and are attacked by the Nemesis. Mikhail sacrifices himself for his squad mates, and detonates an incendiary grenade which knocks the Nemesis out of the tram. The tram loses balance and crashes, luckily into the outside wall of the clock tower. Jill and Carlos manage to ring the bell after solving puzzles to collect an ornate cog piece, as the clock mechanism is missing it. Unfortunately, the helicopter is shot down by the Nemesis and Jill and Carlos fight him. The Nemesis is defeated, collapsing in a fire after his rocket launcher self-destructs due to Carlos' gunfire but during the fight Jill is infected with the t-Virus. Carlos takes her to a chapel within the clock tower for safety.
Later that week on October 1, Carlos heads to Raccoon General Hospital to find a way to save her. Carlos encounters another UBCS member (Tyrell Patrick), who was shot by Nikolai, revealing him as a traitor. He then tries to open a safe booby trapped with explosives.
After creating a t-Virus vaccine from Umbrella machinery and samples, Carlos heads back to Jill. Unaware of what Nikolai has been doing while he was preparing the sample, he is surprised to find that C4 plastic explosives have been planted around the hospital. He manages to escape the building before it is destroyed.
When Carlos injects Jill with the vaccine, The t-Virus in Jill's body is put into a dormant state (and is not destroyed as she believes), and together they head to the nearby public park, hoping to find a new route of escape. Jill finds a small hut in Raccoon Park's cemetery with a secret room, which is being used as a base of operations for the supervisors.
The body of the monitor is found nearby with a bullet in his head, indicating that Nikolai has beaten her here (though Jill is unaware of his treachery). Jill read a file, which explains to the 'supervisors' that Umbrella cannot lobby for more time any longer and that Raccoon City would be destroyed in a missile attack. Jill leaves, but as she does a message is sent through the radio system, telling the deceased operator that the mission has been terminated and that all survivors are to return to base. Nikolai then reveals himself to Jill and prepares to kill her, but a Grave Digger below ground makes Nikolai leave in a hurry. Jill manages to kill the giant worm, and discovers a route to a factory, which turns out to be a waste disposal factory for Umbrella. She and Carlos meet up and find out that there is a helipad with a chopper on it.
Unknowingly stumbling into the waste-processing room, Jill is locked in with the Nemesis and must defeat him and recover a keycard to escape. Leaving just in time, the Nemesis' body is released into a pit containing a corrosive acid.
Depending on choices made by the player before reaching the facility, the chopper can either be piloted by Carlos and Jill escaped with him, or Nikolai beats them to it. If Nikolai steals it, he and Jill exchanged words, with Nikolai taunting them that they won't be leaving and they would die when a thermobaric missile is launched, due to be launched in a couple of minutes. The player also has the choice of destroying the chopper, or attempting to negotiate with Nikolai. Either way, they would not be leaving with that helicopter.
As Jill heads to the helipad, the radar receiver she picks up alerts her to the approaching missile, and at this point the player has 15 minutes to find a way to escape. Jill heads to the helipad, but encounters the Nemesis one final time, heavily mutated after previous defeats, and she defeats it using a large railgun and a magnum. Jill and Carlos both reach the helipad, at a loss of what to do as the sun rises over the city. Another helicopter lands and rescues them - the pilot being Barry Burton (Jill's colleague from Resident Evil).
The city's final fate is resolved in the game's finale. The U.S. government; after hearing of unsuccessful efforts to avert the t-Virus infestation, completely destroys Raccoon City with a thermobaric missile strike.