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Chris Redfield enlists the help of Leon S. Kennedy and Rebecca Chambers to stop a death merchant from spreading a deadly virus in New York.

The saga of Resident Evil continues in Vendetta, and Chris Redfield, Leon Kennedy and Rebecca Chambers must unite to save America from a threat as dire as The Umbrella Corporation: a virus that can be triggered by simply being inhaled. The biological warfare of Resident Evil rages on, and only Raccoon City's finest can stop it from destroying the world.—Johnny

The story follows Chris Redfield as he represents BSAA  in tandem with the military in hunting down Glenn Arias, a global arms dealer who had gain access to a bio weapon: a new zombie virus. In the operation site, Chris' team gets quickly wiped out, and Arias shows him that he had infected Chris' undercover agent friend into a zombie, which can tell friend from foe. Some months later, Ex S.T.A.R.S spec-ops turned scientist Rebecca Chambers is studying the new virus when suddenly her lab is attacked with gas after which everyone else except her turns into zombies. Chris saves her and they share information. Rebecca figured out that the new virus is actually three parts in activation, the main virus, the trigger virus, and the cure vaccine. Chris takes them to recruit Leon Kennedy in continuing the hunt for Arias. Rebecca tells Chris that she tested the vaccine on herself, sparing her from turning into a zombie. She then gives Chris a sample of her blood.

Suddenly Arias' goons attacks and kidnaps Rebecca. We then see that Arias is a survivor from an explosion at his wedding, which killed his wife and family. Arias took Rebecca because she looks so much like Sarah, his late wife. SO he means to redo the wedding. When Rebecca refuses, Arias injects her with an improved version of the new zombie virus. Chris gets info from Rebecca's laptop about the next target for Arias' planned outbreak: New York. He and Leon arrives there and manage to thwart the outbreak threat. Chris and Leon then go to Arias' hideout, where he had been waiting at the roof. Chris dispatches Arias quickly, but he recovers as his monstrous version. Chris manages to wound this monster Arias, but he gets stronger as his biggest goon sacrifices himself and molds with Arias. Chris' team shoots the monster Arias with an energy gun from their Osprey, angering him and making his apparent heart to pulsate with light. Arias jumps to the Osprey but Leon throws out his bike at him, shooting at the fuel tank and exploding it. After that Chris and Leon easily kills Arias by blowing up his heart.