On November 2005, Harvardville Airport falls victim to a T-virus attack both from inside the terminal and a crashlanded airline plane. TerraSave worker Claire Redfield coincidentally runs into Senator Ron Davis; 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 federal agent Leon S. Kennedy. Claire's group is rescued; however, they are forced to leave the infected Greg. Trucks from WilPharma arrive to administer the T-vaccine, but are destroyed by explosives. Leon reveals that a terrorist has threatened to unleash the T-virus throughout the U.S. should government officials involved in its creation not be revealed by midnight.
Claire accompanies WilPharma Head Researcher Frederic Downing to their Harvardville research facility. Downing reveals plans to make a G-virus vaccine next, angering Claire because of its extreme danger. Excusing himself, Downing leaves Claire in his office. Claire informs Leon about what Downing told her, and learns that he and Angela have found the house of her brother Curtis on fire. Downing phones Claire, warning her about a man who has activated a time bomb. Claire briefly spots Curtis in the building's central garden, only for the bomb to detonate.
Leon and Angela arrive at the facility and split up, Leon reunites with Claire, while Angela reunites with Curtis. Curtis reveals the American government's involvement in covering up Raccoon City's destruction. Having injected the G-virus, he mutates and kills a squad of Army Rangers. Leon saves Angela as the atrium garden begins to fall apart, with the wreckage temporarily crushing Curtis. The computer system then incinerates the building in order to prevent the viruses from spreading. Angela and Leon jump into a pool of water to avoid being incinerated. After shooting a glass partition to avoid drowning, the two find themselves in an underground area. Meanwhile, Claire makes it to the command center, attempting to halt a biohazard alarm and open the building. However, the detection of Curtis triggers an outbreak containment method in which the laboratory falls into the abyss.
Curtis attacks them, seeing Leon as a threat and Angela as a mate. Curtis briefly regains control, telling Angela to run before losing himself again. As the sections are ejected, Leon and Angela evade Curtis, 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. In the aftermath, Claire accuses Senator Davis of orchestrating everything in order to improve WilPharma stock. Leon reveals Davis is innocent; making Claire realize that Downing is the actual mastermind of the T-vaccine's destruction, the bombing of the research building, and the recent bioterrorism incidents. Meanwhile, Downing talks to General Grandé, a client of his 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; soon after, he is arrested by the police for his crimes.
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 his name, he wants to prevent another Raccoon City just like she, Leon, and Angela do.
Meanwhile, news reports reveal Davis has resigned from office over allegations of insider stock trading with WilPharma stocks. A newspaper draped over Davis' face reveals that another company, Tricell Incorporated, has offered to purchase the now-bankrupt WilPharma. At this point, Davis is revealed to have been assassinated by Tricell, with the company deleting all of Davis's computer files on WilPharma and recovering G-Virus samples from Curtis's corpse.Paul Mercier as Leon S. Kennedy
Alyson Court as Claire Redfield
Laura Bailey as Angela Miller
Roger Craig Smith as Curtis Miller
Crispin Freeman as Frederic Downing
Mary Elizabeth McGlynn as Rani's aunt
Michelle Ruff as Rani Chawla
Michael Sorich as Senator Ron Davis
Steven Blum as Greg Glenn
Salli Saffioti as Ingrid Hunnigan
The Japanese singer and lyricist Anna Tsuchiya sang the ending theme for the film, titled GUILTY.
The film received a limited (2-week / 3-screen) theatrical release in Japan on October 17, 2008. It also had a limited theatrical release in the United States, opening on November 13 in New York City and November 18 in Los Angeles. A sneak-peek trailer of the first eight minutes of the film was also shown in the North American Home Theater of PlayStation Home.
Resident Evil: Degeneration was released on UMD, DVD, and Blu-ray formats December 24, 2008 (on December 26 in Japan and December 27 in North America). It was later released in the European Union in January–February 2009. More than 1.6 million home video copies were shipped as of September 2010.
The special features include: the "Generation of Degeneration" featurette, character profiles, voice bloopers, a mock-up Leon interview, five trailers, two Resident Evil 5 trailers and previews. In the "Generation of Degeneration" special feature, the filmmakers explain that this movie is in effect "Resident Evil 4.5", i.e. showing what happens after Resident Evil 4.
Nokia and Capcom created a game loosely based on the film for the N-Gage mobile gaming service. This game was released on December 18, 2008, while the iPhone version was released on May 10, 2009. Despite being a main character in the film, Claire is not playable, with Leon being the sole protagonist and playable character in the game. The game takes place in the airport from the early scenes of the film and also contains enemies not seen in the actual film but seen in prior games, such as Cerberuses and the three Tyrants from Resident Evil, Resident Evil 2, and Resident Evil Code: Veronica.
The film received mixed critical reception. The Wired News blog GameLife gave the film 3/10 and the website UGO.com gave the film an overall score of a B. It also held the score of 57% from user ratings at Rotten Tomatoes (19,476 votes). Over 1.6 million DVD and Blu-ray units were sold worldwide.
On September 14, 2010, Capcom and Sony Pictures Entertainment announced a sequel to the movie titled Resident Evil: Damnation, released in 2012. The film stars Leon, with another mystery character and was theatrically released in 3D in Japan.