The movie opens with Alice (Milla Jovovich
), the hero from the last two films, waking up in a shower. She looks around confused and frightened, realizing that she's somehow back in the Spencer Estate in Raccoon City where everything started. She slowly gets out of the shower and puts the red dress laid on the bed on. She exits the bedroom into a hallway and looks around with the distinct feeling of being hunted. She finds her way into the laser room from the first movie, and just before getting cubed she leaps into a vent, crawls through, and drops into.... a hospital corridor. The halls are eerily empty, and Alice stumbles. She grabs a nearby rolling bed to steady herself on, but the bed is promptly cut in two by a giant guillotine (think the blades from that one scene in Indiana Jones and the Last Crusade). She smiles grimly and picks her way past the blade only to get gunned down by a second trap that springs out of the floor and fires bullets in every direction. As her body lies there, three Umbrella scientists approach. One of them is Dr. Issacs (Iain Glen
). He tells the others to take a blood sample of that and get rid of it, which they do by throwing it in an outdoor pit filled with dead Alices. As the scientists do so, we see that this whole facility is but one small part of a giant underground base of the Umbrella Corporation, somewhere in the North American west.
Now Alice -- the real one -- gives us an update from the previous movie 'Resident Evil: Apocalypse'. She tells us that although Umbrella thought Raccoon City was an isolated incident, it soon spread. Within weeks, the T-Virus had spread to the entire North American continent, and within months, the world. It affected everything, killing nearly all plant life and turning the world into a desert. Oceans receded, and lakes and rivers dried up. Humanity was forced to evacuate the cities and stay constantly on the move in order to survive.
We pick up with Alice heading into the ruins of Salt Lake City, Utah on her motorcycle, hearing a broadcast from a radio station that claims to have survivors. She stops outside, takes out her twin machetes, and heads in. The place is zombie-free (so you KNOW the news report is false), and someone is weeping in back. Alice finds an old lady there who says that her "baby is hurtin'", and Alice looks to see....a dead baby. She drops the corpse and is suddenly attacked by all five residents of the station, whom are playing distress calls just to lure other people to their residence in order to kill them and steal their stuff. They throw Alice in a pit lined with cages for zombie dogs and let them loose. Alice does some acrobatics and kills two of the dogs and chains the rest up. Unfortunately, the dogs aren't stopping, so they end up pulling the supports loose and collapsing the floor above, causing their owners to fall into the pit and become kibble as Alice makes a quick escape, pausing only long enough to pick up her weapons on the way out.
Meanwhile, over in Nevada, we see a giant convoy crossing the desert while pumping classic rock music out of their PA system. Two of the members of the convoy are former Umbrella soldiers Carlos (Oded Fehr
) and LJ (Mike Epps
) (from the previous movie) There is some bantering back and forth across the CBs about cigarettes and Carlos's constant yearning for one, and there's an easy sense of familiarity and camaraderie among all the players.
Over in Umbrella's North American HQ, though, things aren't so chipper. Dr. Issacs is coming under fire form his boss, Chairman Albert Wesker (Jason O'Mara
), and the other members of the board of directors for not having a cure to the T-virus that had decimated the entire world. Although other points are discussed, Issacs says that he needs the original Project Alice in order to create a cure since none of the other 86 Alice clones have proven viable. Wesker bluntly tells him that he's got one week and ends the meeting, fading out of existence (all of the board members are communication holograms transmitting from all ends of the Earth.... ain't the five-year future great?).
Meanwhile, Alice is pulling up to a gas station to refuel her motorcycle, but the pumps aren't working since there is no electricity. She heads inside the building and, after a brief encounter with a bunch of flies and a corpse, finds a journal with a bunch of transmission dates and locations inside, including the words, "Alaska safe?" As she heads back out with the journal, she sees a crow with a funny-looking eye watching her and hears a radio broadcast from Mikey (Christopher Egan
) identifying the convoy and their location at a strip motel.
The traveling convoy arrives at the deserted motel. The exterior is safe, and Carlos and LJ go inside to check things out. Carlos clears the front office as LJ does the rooms, all of which are locked tight.... except for one with a busted lock. LJ heads inside and peeps around, but a zombie gets the drop on him. After a tussle, he shoots it....deader....and takes a breather before seeing another in the distance. As it rushes towards him, he fires and...hits the mirror. He turns quickly and the zombie woman is on him. He struggles, but she gets him in the chest (right lung area) just as Carlos comes in. Betty (Ashanti
) checks him out and pronounces him fine as Carlos walks away trying not to puke. The two flirt and Betty leaves. LJ sighs as he stares after her, and then pulls his shirt back to see the ugly looking bite souvenir the zombie left him.
That night, we see Carlos setting up the last of some surveillance monitors for Mikey as Otto (Joe Hursley
) hands out one can of dinner to everyone, including two for Betty (one's for LJ though, so it's cool). Later, we see Claire (Ali Larter
) and Carlos talking, and it's pretty obvious that Claire is growing tired of moving around all the time.
Elsewhere, Alice is fitfully sleeping in the desert as she dreams about her latest dupe being killed. As she does, she accidentally starts levitating everything around her with telekinesis until she wakes up, at which point everything falls back down.... including her bike, which is wrecked. As she sighs and reluctantly decides that her only choice now is to meet up with that convoy.
Meanwhile, Dr. Issacs is seen in his underground lab, where the White Queen (Madeline Carroll
) holographic computer model informs him that a burst of psionic activity was just detected in the Nevada desert. He realizes that this could mean Alice, but before he can do anything his immediate superior, a man named Slater (Matthew Marsden
) comes in. The two squabble about company policy and the readiness of Alice Clone Number 87, and Slater leaves, having asserted himself. Beaten, Issacs goes over to a test section where they have a zombie chained up that has been injected with some of Alice's blood. Remarkably, the thing is quite adept, recognizing the cell phone and taking a picture of the two lab assistants with a camera. As the assistants start congratulating Issacs, though, the zombie becomes frustrated at a shape-recognition test, breaks free, and attacks the assistants a quicker Issacs locked in with it. As he watches the slaughter, he gets a look on his face that is best interpreted as, "Well....I feel better now."
The next day dawns, and we see Alice walking through the desert. Meanwhile, K-Mart (Spencer Locke
) wakes up from a nightmare and hears... something. She wakes up Claire, and they see enough infected crows to give Alfred Hitchcock bad dreams. Claire quietly radios everyone to pack up and leave as quickly and quietly as possible. The crows ignore the movement and the engines...but than a kid on the school bus drops his can, and the game is on. The crows attack everyone nonstop, and lots of people get killed, including Otto and Betty. At one point, the bus ends up crashing, and the crows gather around it. Claire and Carlos get something set up that gets some kids transferred to Mikey's van, but a few others fall off, including one that gets separated, and as Claire and LJ run for her shooting guns at the crows and Chase mans a giant flamethrower to create a bunch of crispy critters, Carlos reaches the runner and covers her with his body as the flames.... stop five feet short of him. Wondering why he isn't burning, he looks up... and sees Alice, staring down the fire while projecting a psychic bubble to keep them safe. The last of the crows gets burned, and Alice releases the bubble. As everyone else, including Claire, gathers round, Carlos and Alice hug at the joy of seeing each other again.
At Issac's lab, he gets visited by Slater just as Alice Clone 87 is going through the test routine. As she gets chowed on by one of the super-smart zombies, Issacs shows to Slater a whole group of about a dozen smart-zombies just waiting for release and says that the serum derived so far is actually making them stronger. At that moment, the White Queen informs Isscas of another burst of psionic activity in the desert and says that there is a 62% chance that it's Alice -- too great to pass up, in his opinion, although Slater says that Wesker won't approve.
Meanwhile, Alice wakes up in a tent and finds herself being observed by K-Mart, who when asked says that that's where they found her and since she didn't like her other name much and everyone else she knew was dead, that's what she's called. Carlos greets her again and takes her outside, where the convoy survivors have just finished burying their dead. He introduces her to Claire and the two get along, although there is some tension between them. After a while, Alice tells the main bosses (everyone who's been given a name) about Alaska, and since Claire feels it's too big for her to decide, she has the group vote, and it's pretty much unanimous. Unfortunately, this means they have to go somewhere and stop for gas, and the nearest place that would have enough is Las Vegas.
That night, as most of the group sleeps and LJ picks at his ever-worsening bite, Alice flips through the journal and comes to a page that says, "Keep on laughing. Keep on living. Keep on loving." She pauses and gets a dreamy look in her eye.
Meanwhile, Issacs is in a meeting with Wesker over the communications hologram to try and get some Umbrella troops to move on the Alice situation, but Wesker will have none of it, ordering Issacs to continue with the cure research. However, Issacs managed to record some of their conversation, and uses a dupe of Wesker's voice to authorize the release of troops. A large group of Umbrella troops arrives at the besieged facility by helicopter with a large cate for transport.
The next morning, everyone starts heading for Vegas. On the way, Chase comments to LJ how he isn't looking too hot, but LJ just brushes it off. They pull into Vegas, but the entire city is buried under massive sand drifts. As Chase takes up a lookout position on a copy of the Eiffel Tower as a marksman, the rest disembark to move some giant crate that's blocking the way. Suddenly, a bunch of super-fast, smart-zombies burst out and proceed to tear into everyone. Chase manages to hold some off, but he ends up having to help this one girl climb up to his position, only the zombies end up biting him and he throws everybody off the tower. LJ and K-Mart take refuge in a van where she wields a shotgun pretty good, but LJ soon turns and is forced to be put down by Carlos, who himself gets bitten by LJ. Mikey is separated and eaten at some point as an anguished Claire watches as she tries to save him. As for Alice, she is slicing and dicing like crazy when suddenly a nearby rooftop team of Umbrella techs, including Issacs, shuts her down. Unfortunately for them, she fights the command, wakes back up, and leads a bunch of zombies to them. Issacs boards the helicopter and escapes, but not before getting bit. Alice puts the last super zombie down and holds her guns on the copter, but doesn't shoot. Issacs, for his part, is placed under house arrest by the soldiers as soon as he arrives back at his lab. Slater strides up to him to see that he's injected himself with about ten vials of his serum and informs him that he's fired by way of gun. Issacs falls, but then gets right back up and inserts a bunch of tentacles into Slater's face.
A little while later, Carlos, K-Mart, Claire, and Alice have tracked the helicopter to the hidden Umbrella base, and Carlos volunteers for a suicide mission wherein he drives a large fuel truck into the midst of the thousands of zombies piled against the fence and blows it up with a smile on his face. Alice, K-Mart, Claire, and the remaining kids drive through the wreckage and through the massive crowd of zombies. As Alice gets everyone loaded onto a helicopter, she throws the journal at K-Mart and says, "Take care of them." She shares a look with Claire and the group is off in the helicopter as Alice stays behind to fight the Umbrella techs.
Alice heads inside the underground facility, passing the rejected Alice clones and nearly throwing up. She then heads down into the complex, which is now a massive ruin. As she pokes around, the White Queen appears before her, identifying herself. Alice just smiles and says, "Yeah, I knew your sister....she was a homicidal bitch." The White Queen explains that Issacs is contained on the lower levels and that Alice's blood can be used to synthesize a permanent cure for the T-Virus. She then opens up an elevator, wishes Alice luck, and sends her down to the labs. Upon her arrival, Alice sees Alice Clone Number 88 resting in a stasis bubble and nearing completion. The bubble bursts as Alice touches it and Clone 88 sits up, gasping and looking at Alice in confusion just before falling unconscious. Saddened at her death, Alice takes off her coat and covers the clone with it just as a heavily mutated Issacs leaps out. They fight each other into the mansion area with Alice barely holding him off with a psionic bubble. Eventually they end up in the laser room with Issacs proclaiming himself the future, and Alice just laughs and says that their both about to die. The cube sequence starts, and Issacs gets cubed, but just before the lazers take Alice they stop advancing and the room shuts down. Back in the lab, Clone 88 -- who is apparently less dead than previously thought -- just stares at the screen, shuts down the system, and says, "Yeah, you're the future all right....asshole."
Miles away in Tokyo, Wesker is holding another hologram meeting with his branch of Umbrella members of the board. He informs the other directors that the North American facility is compromised, and all of its research will now be under his direct supervision. He declares that finding and bringing in Alice is now their number one priority when suddenly Alice appears as a hologram from the North American lab and warns them that she's coming for them, and that she'll be bringing a few friends of hers along. She signs off and walks over to a window where 88 is waiting. The two look at each other and then gaze out in wonder over the vast field of backup Alices, all of which are waking up and looking extremely hungry for battle...