In the year 2005, the Harvardville Airport is under attack by a zombie infestation. Claire Redfield is now a member of TerraSave, an organization which handles search and rescue at chemical and biological attacks. Claire was on-site to meet a family she is aiding, and coincidentally runs into U.S. Senator Ron Davis, who was trying to avoid protesters. Meanwhile, a passenger aircraft approaching the airport crashlands due to a man infected with the T-virus, who caused an infestation on-board. Unable to escape from the airport terminal, Claire, Rani and Davis shut themselves in the VIP lounge and call for help.
By nightfall, the airport has been locked down by the local Special Response Team and the United States Marine Corps, aiding evacuated survivors. Two officers Angela Miller and Greg Glenn, are joined by Leon S. Kennedy. The group enter the building where Claire's group is hiding through the roof and manage to find them. Traveling back to the main terminal, Glenn is bitten by an infected and stays behind, determined to save the rest by holding off the undead. The survivors shoot their way out, with the U.S. Marines (who had been vaccinated prior to the lockdown) clearing out the terminal.
Claire sees a convoy of trucks from the WilPharma Corporation, who she was campaigning against. Upon being told that WilPharma had created a T-virus vaccine, Claire realizes that the vaccine could have saved those who died. Suddenly, the WilPharma trucks containing the vaccine are destroyed. Claire accompanies WilPharma chief researcher Frederic Downing to the WilPharma research facility for more vaccines. After a tour of the facility, Claire is shown a molecular-scale image of the G-virus. Downing, surprised by her anger, excuses himself and she is left alone in his office.
Claire calls Leon to inform him about WilPharma's possession of the G-virus, and learns that he and Angela Miller have found the house of Curtis Miller, Angela's brother, destroyed by fire. Downing phones Claire to warn her that a man has just left the facility and that a time bomb has been activated. Claire catches a brief glimpse of Curtis Miller through a window, only for the bomb to detonate.
Leon and Angela arrive at WilPharma and Leon goes upstairs to Claire while Angela, monitoring the ground level, encounters Curtis. Curtis tells Angela that the government covered up some of the events in Raccoon City which kept his family from being saved. A squad of Marines storm the room. Curtis, having injected the G-virus, mutates and attacks the Marines. Leon saves Angela as the atrium garden begins to fall apart, with the wreckage crushing Curtis. Believing him to be dead, the surviving Marines head up the elevator to safety, Curtis however gets out of the wreckage and mutates further, climbing up the building and destroying the elevator.
The WilPharma computer system then sets the building on fire in an attempt to avoid the T- and G-Virus' spreading. Angela and Leon jump into a pool of water to avoid being incinerated. After having shot a glass partition to avoid drowning, the two find themselves in an underground area. Meanwhile, Claire makes it to the command center on the topmost floor, doing whatever she can to halt a biohazard alarm and open the building. However, The detection of Curtis in the underground center causes another alarm, in which sections of the building are ejected to fall deep underground.
As Leon and Angela search for an escape route, Curtis attacks them, seeing Leon as a threat and Angela as a mate. Eventually, Curtis manages to regain control, telling Angela to run. As the sections are being ejected, Leon and Angela climb up wreckage, only to hang from a broken catwalk. About to fall, Curtis grabs hold of Angela's leg but is shot by Leon in the head and fall to his death. The impact of Curtis with the bottom of the pit causes an eruption of fire, from which Leon and Angela are saved when a bulkhead closes just below them.
Leon, Angela and Claire exit the building. There Claire accuses Senator Davis of the cover up and the Harvardville Airport incident. Leon reveals that Davis did not know anything, and Claire realizes that Downing engineered the outbreaks in the airport and the airliner, as well as the destruction of the vaccine, the bombing of the research building and the bio-terrorism incidents by selling T-virus samples. Meanwhile, Downing talks to General Grandé, a client eager to buy the T-virus, now that news reports have revealed its potential. Waiting for a contact to sell WilPharma information to, Downing mistakes a car containing Leon and Claire for his contact. He is arrested by Angela.
The next day Leon and Claire meet with a despondent Angela. Leon reveals that Downing confessed to everything, which was designed as a sales pitch for the virus to General Grandé. He reveals that he was an Umbrella researcher and stole samples of both viruses and escaped immediately prior to the Raccoon City incident before erasing his history and creating a new identity with which to apply to WilPharma. Once there, he was able to sell the virus to a list of potential customers while researching the vaccine.
Leon, Claire, and Angela go their separate ways. Meanwhile, news gets out that Davis has resigned from office over allegations of insider stock trading with WilPharma stocks. A newspaper draped over Davis' face reads "Tricell Offers to Purchase WilPharma". Davis' hand falls from the desk revealing him to be dead, and on his computer WilPharma files are being deleted, which when completed reveal a Tricell, Inc. insignia on his screen.
The film ends with Tricell employees in hazmat suits searching the underground ruins of the WilPharma research building, where they discover a fragment of Curtis's body infected with the G-virus, which they seal in a biohazard container.
