The third novel starts with an introduction of newspaper articles (as in the first two novels) detailing information in the setting. Raccoon City is revealed to be hiring at least ten to fifteen new officers in response to the city's worries about the attacks that plagued it a few months before. The local S.T.A.R.S. branch has been disbanded thanks to Umbrella's influence, and are no longer present in the city. The last article details an attack on a woman by a supposed "drunk" stranger...
On the night of October 3, Leon Kennedy, a rookie officer, is due to arrive at Raccoon City that day, but winds up being late, due to over sleeping, and New York traffic. As he heads to the city, he muses over the cannibal attacks, and aspires to solve the attacks shortly after he arrives. Lost in his thoughts, he nearly has an accident as a zombie dog runs in front of his jeep. As he arrives in Raccoon City, he notices that the city is seemingly abandoned. Not knowing why, he sees a flock of crows leave the corpse of a partially devoured woman in the street. After examining the woman, he hears groans behind him, and is surrounded by zombies.
Meanwhile, Claire Redfield is on her way into Raccoon City, looking for her brother, Chris. She thinks over the lack of contact with Chris, and about the trouble with reaching him, noting that the lines seemed to be dead when calling anyone in Raccoon. Arriving in the city, she notes the city is abandoned as well, and stops at the diner where she and Chris usually meet when she frequently visits him however, the diner is empty. As she's about to leave, she hears a grunt in the corner. The grunt is revealed to be coming from a zombie as it devours a waitress. Claire is about to flee, when she sees that more zombies have assembled outside the front door. As she flees through the back door, she meets Leon. They run to a police car as zombies slowly outnumber them, before speeding down the streets. Unbeknown to them, a zombie was in the backseat, Leon purposefully crashes the car to keep it from biting Claire. As they recover, they see a truck speeding toward them, both escape by mere seconds before they're separated by the resulting explosion. Leon tells Claire to head to the police station and that they'll meet up later. Both make their way to the Police Department. Leon reaches the police department via the streets behind a gun shop, whose owner has been recently killed by zombies.
At the end, the S.T.A.R.S. Exeter, Maine branch arrive and evacuate the survivors.