Synopsis

After the Raccoon City Incident in 2002, the T-Virus escaped containment despite the nuclear destruction of the city. The Umbrella Corporation desperately tries to stop it from turning the entire world's population into zombies, but after a series of viral outbreaks over the past 5 years, the world is on the verge of extinction.

Alice (Milla Jovovich), Umbrella's greatest Bio-Organic Weapon, is now alone in the desert wastelands of the remains of the United States after learning that the corporation has the ability to track her location via satellite. She has super-human strength and psychokinetic abilities gained from her brief imprisonment by Umbrella, and because of her ability to bond with the T-virus, the corporation seeks to develop a permanent cure to the T-Virus to save what is left of humanity. Under the orders of Umbrella chief Albert Wesker, Dr. Sam Isaacs attempts to create a cure without Alice, using clones created from her blood; the clones endure tests within re-created Spencer Mansion, The Hive, and Raccoon City Hospital locations, but none survive.

After Alice has a run in with zombie dogs, she leaves for a gas station near the ruins of Las Vegas and finds a journal detailing a route to Alaska where the infection is suspected to be almost non-existent. Meanwhile, Claire Redfield's (Ali Larter) convoy, which includes fellow Raccoon survivors Carlos Olivera (Oded Fehr) and L.J. (Mike Epps), along with new survivors K-Mart (Spencer Locke), Mikey (Egan) and Nurse Betty (Ashanti), search a small motel for supplies. L.J. is bitten, but does not tell Nurse Betty, who checks his other wounds. The next morning K-Mart wakes up and hears noises on the car. She opens the door and an infected crow screeches at her. After climbing back in, she wakes Claire, who when radios all of the vehicles to quietly put up the windows. As the others wake up, they see thousands of infected crows surrounding them. Claire explains their presence, saying they've been feeding on infected flesh. A soda can is dropped, alerting the crows to attack. Carlos is about to be killed, when Alice arrives. She uses her telekinesis to utilize the flamethrower and covers the sky in fire while simultaneously keeping the convoy safe. Despite her efforts, Nurse Betty and a few others die in the attack.

Alice is introduced to Claire, and the leaders of the group decide to search for supplies in Las Vegas. At the Umbrella corporation, with the help of a new artificial intelligence computer called the White Queen, they are able to pick up Alice's location based on the use of her power. Dr. Isaacs orders a crate of super zombies, created from cloned Alice's blood, to be transported to the convoy's destination against Wesker's wishes. The convoy meet with the new zombies and a battle between them ensues. Mikey is killed along with a large portion of the convoy in the fight, while L.J. turns into a zombie and bites Carlos before being shot down. Once Umbrella sees Alice is in position, they attempt to "shut her down" and control her actions. She resists the attempt and continues to come for Isaacs, getting to his location just as he slips away in a helicopter. She refrains from shooting the helicopter in order to later use it as transport to Alaska.

The remaining members of the convoy head towards the Umbrella facility, but they find it surrounded by thousands of zombies. Carlos believes the infection inside himself has gone beyond a cure, and then sacrifices himself for the convoy. Alice and Carlos kiss before he departs, using a gasoline transport truck to drive into the zombies. He detonates the dynamite and after the explosion, the group move in through the opening made by Carlos's sacrifice. They depart on the helicopter piloted by Claire. Alice stays behind, however, planning to exact her revenge on the Umbrella Corporation. Dr. Isaacs has been bitten by a super zombie and has mutated into a monster, the Tyrant. After Wesker's orders to have him killed fail, Isaacs goes on to kill all the employees in the facility. The White Queen manages to trap Isaacs in the lower levels and instructs Alice that she must pass through there to create a cure.

Alice heads down, seeing a clone of herself still in a vegetative state. She examines it, but Isaacs interrupts, attacking Alice before fleeing when she stabs him with a khukri knife. The clone then awakens, seemingly dying in Alice's arms. She covers the clone in her coat and leaves after Isaacs. In the replica of the Spencer Mansion, a battle between Isaacs and Alice ensues, both displaying use of telekinesis. When the fight is taken to a replica of the laser room from The Hive, Alice informs him that they are both to die there when the lasers activate. The lasers cut Isaacs into pieces in the same fashion as the character One in Resident Evil, and just as Alice is about to meet the same fate, the lasers dissipate. The clone of Alice is shown to be the one who turned off the lasers.

Meanwhile, in Tokyo, Japan Wesker informs the rest of the Umbrella board that the North American branch has been lost, and he will now control further scientific experimentation from Japan. Using holographic technology, Alice makes an appearance at the meeting, saying that she and her friends are coming for them now. Standing beside the clone of herself, Alice looks onto the rows of pods containing the other clones, their numbers in the hundreds. As many clones begin to awake, the film ends.