A US Navy submarine goes missing after reporting an attack by an unidentified entity.
Ada Wong attacks the submarine Simmons told her to go to. Simmons was actually Carla Radames in disguise as Carla wanted Ada to know about the attacks that happened six months ago in Edonia and a future attack that will happen in two days time. Ada escapes the submarine via a torpedo moments before impact.
After six months of searching Eastern Europe, Piers Nivans and a number of other B.S.A.A. operatives finally find AWOL Captain Chris Redfield, a drunked wreck of his former self who has forced himself to forget his anti-terrorism career.
At the same time US President Adam Benford is infected with a mutagenic virus in a bioterrorist attack on Tall Oaks. He is mercy-killed by Leon Scott Kennedy. Leon and Helena Harper escape Tall Oaks with a group of survivors before being ambushed by zombies leaving the other survivors killed. They reach Tall Oaks Cathedral and uncover an underground lab. They also find Ada and Helena's sister Deborah Harper, but Deborah undergoes a transformation and is killed. Ada learns about Carla's origins and that she was the one contacting her instead of Simmons. Leon and Helena escape the city via the old Simmons family's catacombs as Tall Oaks is destroyed by missiles just like Raccoon City.
Jake Muller and Sherry Birkin escape from a Neo-Umbrella lab but are later captured again and put into the underground facility. BSAA Operative Marco Rose was killed by Carla Radames and BSAA Operatives Jeff, Keaton and Reid were all killed by the Iluzja. Chris enraged by this continues his search for Ada, who is actually Carla. They eventually find Carla, on a ship owned by Neo-Umbrella, where she tells her plan to spread the C-virus world wide. She is then shot by Derek C. Simmons men. Chris and Piers head to attempt to stop the missle which they fail.
Meanwhile, Ada finds Carla body, only to find that she infected herself with the virus. Ada defeats Carla and goes to finish off Simmons.
Leon tells Chris that Jake and Sherry have been kinapped. Chris and Piers find them and let them escape while they fight a B.O.W. Haos. Piers infects himself with the C-virus to save Chris and decides to stay behide in the sinking facility.Jake and Sherry are persued by Ustanak which they finally defeat.
Leon and Helena fight Simmons with Ada. Simmons is defeated, where Leon and Helena escape by helicopter left by Ada, while Ada destroys Carla's work and escapes by unknown means.
Leon and Helena are at the grave of Deborah Harper and she is forgiven for her involement in the attacks.
Chris is seen at the bar where he was on June 29th. He continues his career as a BSAA captain.
Sherry is on board a plane where Jake sends a message that he is selling his blood for $50. He is later seen in the middle-east fighting B.O.W.s.