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.
BSAA captain Chris Redfield and his team enter China and fend off the bioterrorism threat that is occurring in Waiyip. They rescue United Nations hostages in a tenement and escape the tenement as it is destroyed. Chris sees the remaining cocoons and remembers what happened to his old teammates six months ago. He attempts to pursue Ada Wong. Along the way, 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. Chris and Piers run into Leon and Helena. Chris and Piers chase after Carla while Leon and Helena pursue Simmons.
Meanwhile, Ada Wong makes her way to China and comes across some J'avos before coming face to face with the Ubistvo. She manages to escape it and knock it over a ledge on the train tracks. Jake and Sherry are then attacked by the Ubistvo, but escape it. At the same time, Leon and Helena board a plane to China, but are attacked by a Lepotitsa causing the plane to be infected with the C-virus. Leon takes control of the plane, but ends up crashing it in a cargo field. Leon and Helena survive the crash and they find Jake and Sherry and together all four fend off the Ustanak. Leon and Helena make their way through a market while escaping the Rasklapanje. Jake and Sherry are again pursued by the Ubistvo, but manage to defeat it while being rescued by Ada Wong. Ada escapes on a jet ski. Leon and Helena find Chris and Piers and they agree to chase down Simmons while the BSAA will track Ada (Carla). Jake and Sherry find Leon and Helena again in a warehouse and find Simmons who attempts to arrest Leon and Helena. Jake and Sherry are eventually captured and taken to an underwater Neo-Umbrella facility. Leon and Helena chase after Simmons and defeat him on a subway train. They eventually make their way towards Tatchi.
Chris and Piers stumble on an aircraft carrier owned by Neo-Umbrella and eventually find Carla. 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 as another missile is aimed at Tatchi, which infects the entire population with the C-virus.
Meanwhile, Ada finds Carla's body on the aircraft carrier, 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 abducted. 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 behind in the sinking facility to prevent him losing consciousness due to the virus. Jake and Sherry are pursued by the Ustanak and they finally defeat it on a runaway underground train, which they also use to escape the facility.
Leon and Helena attempt to escape the infected Tatchi before finding Ada Wong alive in a helicopter. Together, they manage to reach the quad tower and fight the mutated Simmons. Simmons is transformed into a giant fly and is eventually defeated by a rocket launcher that Ada gave to Leon and Helena. In addition, Ada gives them her escape helicopter. 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 29. 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.