Following the outbreak of the T-virus in Raccoon City and its subsequent destruction by nuclear bomb, the Umbrella Corporation goes under and is bought by WilPharma, a pharmaceutical company. WilPharma soon comes under fire after another T-virus outbreak occurs in India.
In 2005, the Harvardville Airport is under attack by a zombie infestation, both from inside the building and an infected airplane that crashes into the terminal. On-site TerraSave agent Claire Redfield coincidentally runs into Senator Ron Davis, who was trying to avoid protesters; they are forced to hide in the VIP lounge with Rani, niece of a TerraSave employee. By nightfall, the airport has been locked down by the local Special Response Team and the United States Marine Corps, aiding evacuated survivors. Officers Angela Miller and Greg Glenn are joined by Leon S. Kennedy. Leon and Miller manage to save Claire’s group; however, they are forced to leave Greg, who was infected during the escape. Trucks from WilPharma arrive to administer the T-vaccine; however, they suddenly explode.
Claire accompanies WilPharma chief researcher Frederic Downing to the research facility for more vaccines. Downing reveals they plan to make a vaccine to the G-virus next, angering Claire; she knows first-hand it’s extremely dangerous. Excusing himself, Downing leaves Claire in his office. Claire informs Leon about WilPharma’s possession of the G-virus, and learns that he and Angela have found the house of her brother, Curtis, burned down. Downing phones Claire, warning that he tailed a suspicious man, who has activated a time bomb. Claire catches a brief glimpse of Curtis through a window, only for the bomb to detonate.
Leon and Angela arrive at WilPharma and split up. Leon regroups with Claire, while Angela reunites with Curtis. Curtis explains the government covered the truth about Raccoon City. 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. However, Curtis mutates further, and destroys 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.
Curtis attacks them, seeing Leon as a threat and Angela as a mate. Curtis manages to briefly regain control, telling Angela to run before losing himself again. As the sections are 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 in the head by Leon, and falls 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. In the aftermath, Claire accuses Senator Davis of being part of the cover up and the Harvardville Airport incident. Leon reveals Davis didn’t know anything, and Claire realizes that Downing engineered the outbreaks, 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 Grande, a client eager to buy the T-virus, now that news reports have revealed its potential, though he warns against using the G-virus. Waiting for a contact to sell WilPharma information to, Downing mistakes a car containing Leon and Claire for his contact. After failing to bribe them, Downing is arrested by Angela.
The next day Leon and Claire meet with a despondent Angela. Leon reveals Downing confessed to being a former Umbrella researcher who stole both viruses and escaped prior to the Raccoon City incident and created his current identity. Downing used his alias to sell the viruses to a list of potential customers while researching the vaccine. Angela realizes Downing manipulated Curtis, but Claire notes that even though this does not clear Curtis’s name, he had the same motives to prevent another disaster like Raccoon City as she, Leon, and Angela do.
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.