The player takes control of former S.T.A.R.S. officer Jill Valentine in her attempt to escape a ruined and zombie-infested Raccoon City. During her escape, she encounters three surviving members of the Umbrella Biohazard Countermeasure Service, Carlos Oliveira, Mikhail Victor and Nicholai Ginovaef. Mikhail sacrifices himself to save Jill from the Nemesis, a bio-organic weapon, and Jill escapes with Carlos. Depending on the player’s actions, Nicholai may also die.

Nemesis was the last core title in the series to be released for the PlayStation and it was also the final Resident Evil game to take place in or around Raccoon City until the release of Resident Evil Outbreak. The city’s fate is resolved in the game’s finale. The US Government, after hearing of unsuccessful efforts to avert the T-Virus infestation, orders the destruction of Raccoon City. At this point in the game, the player has exactly fifteen minutes to escape the city before the missile strikes.