Alice (Milla Jovovich) and her vast army of clones assault the headquarters of Umbrella Corporation in Tokyo, killing everyone in charge except Albert Wesker (Shawn Roberts), who escapes in a tiltrotor plane and sets off a bomb that leaves a huge sinkhole where the headquarters had been. The real Alice had boarded the plane and tries to kill Wesker, but he injects her with an anti-virus that removes all her superhuman powers. It seems that Wesker reversed that process for himself, using the T-virus to obtain supernatural powers. Just as he is about to kill Alice, the autopilot crashes the plane into the mountains.
Six months later, Alice is flying to Alaska, tracking broadcasts from a safe haven there called Arcadia. She finds only abandoned aircraft and is attacked by a feral Claire Redfield (Ali Larter). Alice destroys a chest-scarab, a spider-like device on Claire’s chest, which frees her, but she has amnesia. They travel to a ruined Los Angeles, where survivors in a prison are surrounded by thousands of zombies. Luther West (Boris Kodjoe) is leading Wendell (Fulvio Cecere), Crystal Waters (Kacey Barnfield), Bennett Sinclair (Kim Coates), Kim Yong (Norman Yeung), and Angel Ortiz (Sergio Peris-Mencheta). They help Alice land on the roof and she learns that the real Arcadia is not on land but is a cargo tanker off the coast.
The ship has not responded to their message flares. Luther introduces Alice to Chris Redfield (Wentworth Miller), Claire’s older brother, a soldier who says he was falsely imprisoned and will help them escape if they set him free. Alice goes to the showers and catches Wendall trying to spy on her. They are attacked by a group of infected that dug into the prison who capture Wendell, but Alice holds them off.
The group escapes the prison with Chris in an armored car, but a giant axe-wielding monster (Ray Olubowale) smashes the gate. Alice, Chris, and Crystal go to the armory in the basement for more firepower, but zombies kill Crystal. Luther and Claire reinforce the gate and Angel points out to Bennett and Yong that the car they wish to use has no engine. Bennett shoots Angel and heads for Arcadia in Alice’s plane. The Axeman breaks down the gate and the zombies rush in. Alice’s group decide to use the tunnels to escape into the sewers. Yong is killed by the Axeman and Alice is knocked out. Claire distracts the Axeman and Alice comes to and kills it, but Luther is dragged into the tunnels by a zombie.
Alice and the Redfields board the Arcadia and find it abandoned. The plane has crashed on the deck. Claire remembers that Arcadia was built as an Umbrella trap to obtain test subjects. They release the survivors, including K-Mart (Spencer Locke). Alice follows a trail of blood and finds Wesker, alive and transformed, not a monster. The T-virus revived him but he is battling it for control of his mind. He thinks he needs fresh human DNA. The Umbrella staff all fled when he began eating test subjects. He thinks he should eat Alice to obtain her superior DNA.
The Redfields battle Wesker and Alice battles Bennett, who is now on Wesker’s side. Wesker overpowers Chris and Claire, but with K-Mart’s help, Alice defeats both Bennett and Wesker. Wesker abandons Bennet to his zombie dogs and escapes in a plane, leaving a bomb behind on the Arcadia, but Alice had found the bomb and put it on the plane, which explodes. Wesker uses a parachute to escape and Luther emerges victorious from the sewers. Alice vows to turn Arcadia into a haven for survivors and broadcasts a message of welcome. Alice, Claire, and Chris watch as a squadron of Umbrella aircraft approach, commanded by Jill Valentine (Sienna Guillory) controlled by an Umbrella chest-scarab.
The film was written and directed by Paul W.S. Anderson, who had directed the first film of the series, based on the Resident Evil videogame. It was the first to be shot in 3-D, using James Cameron’s camera system. It received mixed reviews, cost 60 million and made that back in the U.S., plus another 240 million in the rest of the world. Most of the filming was done in Toronto and a scene involving a plane crash caused many people to call the police. Robarts Library at the University of Toronto played the prison because it looked so prison-like. During filming, Milla Jovovich shot dead a $100,000 camera. Anderson wanted an upbeat ending, but the studio insisted on the cliff-hanger. The film was not released to critics for review, since their usual opinion was that the series was terrible, unnecessary, and a dreadful bore. Too bad the public had not read the reviews before wasting 300 million dollars enjoying it.