Ada Wong infiltrates the "missing" submarine on behalf of the National Security Advisor Derek C. Simmons (actually Carla Radames in disguise). Ada is informed of a series of terrorist attacks orchestrated by Neo Umbrella, before making her escape in the events of a hull breach. Ada escapes the submarine via a torpedo moments before impact.
After six months of searching Eastern Europe, Piers Nivans and a number of other BSAA operatives finally find AWOL Captain Chris Redfield, a drunk wreck of his former self who has forced himself to forget his anti-terrorism career.
US President Adam Benford is about to held a press conference to reveal the secret dealings between Umbrella Corporation and US government. He asked DSO agent Leon Scott Kennedy about his opinion, to which Leon chose to stand with Benford's decision.
Derek C. Simmons, head of The Family fraternity, attempted to dissuade the president from doing such controversial act, to no avail. He forced CIA agent Helena Harper to leak the C-Virus to stop the president, under the threat of seeing her sister, Deborah Harper, executed.
President Adam Benford was infected with the C-Virus virus in a bioterrorist attack on Tall Oaks. He is mercy-killed by Leon. Leon, aided by Helena Harper, escape Tall Oaks through the subway system before teaming up with a group of survivors. All survivors except Leon and Helena were killed in the ensuing accident.
The agents reach Tall Oaks Cathedral and uncover an underground lab. They also find Ada Wong and Helena's sister Deborah, but she undergoes a mutation and is killed.
Simmons declared Leon and Helena as the terrorists, and had their names listed as top suspects.
Ada learns about Carla's origins and that she was the one contacting her instead of Simmons. She destroyed the underground laboratory and heads to China.
Leon and Helena escape the city via the old Simmons family's catacombs.
Simmons ordered his men to bombed Tall Oaks, eradicating any evidence.
BSAA captain Chris Redfield and Alpha Team enter China and fend off the bioterrorism threat that is occurring in Waiyip. Alpha Team crossed paths with Jake and Sherry, the latter being surrounded by an army of J'avo.
Alpha Team is swiftly annihilated by Neo Umbrella's Iluzija. Chris and Piers are the only survivor of the attack and track down Carla Radames.
Ada Wong arrives to see China being ravaged by bioterrorists. She battles and narrowly escapes the murderous Ubistvo.
Agents Leon S. Kennedy and Helena Harper boards a plane to China. A Lepotitsa B.O.W. hatches in the plane's cockpit and releases C-Virus gas to infect every passenger. After ejecting the creature off board, the agents crash-landed the plane.
Leon and Helena aid Jake and Sherry to defeat the Ustanak, and later part ways.
The US agents chase down a female individual, believed to be Ada Wong. They cross paths with BSAA agents Chris Redfield and Piers Nivans. They agree to fight towards a common goal; the BSAA will capture "Ada Wong", and the US agents will arrest Simmons. Chris and Piers chase Carla Radames all the way to her private aircraft carrier.
The real Ada Wong scouts Jake Muller and Sherry Birkin, helping them in the shadows against the chainsaw-handed Ubistvo.
The agents briefly join forces with agent Birkin during their encounter with Derek Simmons and The Family, who reveals his malevolent nature. Simmons is shot with a C-Virus vial by Carla's J'avo. Leon and Helena goes after his, jumping on a fast-moving train. Simmons mutates into a B.O.W., but is put down by them. Jake and Sherry are apprehended by more J'avo and taken into Neo Umbrella Seabed Laboratory.
The BSAA agents search for Carla through her carrier. They discover her, plotting to launch missiles loaded with C-Virus gas to infect the whole world. Members of The Family shoot her on the torso, killing her. They then proceed to the hangar, piloting one VTOL to destroy the C-Virus missiles.
Meanwhile, Ada herself had infiltrated the carrier much earlier than the agents. She discovers Carla's files and records of her "rebirth". She eventually fights Carla's uncontrollable mutation, putting her out of her misery. Ada then heads to the mainland.
One of the missiles strikes Tatchi, releasing C-Virus which turns thousands of its inhabitants and refugees into zombies. BSAA operatives are ordered to pull out. After Simmons' apparent defeat, Ingrid Hannigan informs Leon that agent Birkin was kidnapped and taken into the Seabed Laboratory. Leon informs Chris of the situation.
Chris and Piers find Jake and Sherry, the latter are separated when a B.O.W. Haos, attacks them. After being injured by the creature, Piers infects himself with the C-virus to save Chris and decides to stay behind to prevent him losing consciousness to the virus. Both he and the Haos are killed in the facility's destruction.
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 are forced to fight Simmons, mutating endlessly until his demise, with the help of Ada Wong. They escape the Quad Tower using the helicopter Ada left earlier.
Continuing her own mission, Ada makes her way into Carla's laboratory where her final creation resides. Ada uses her Ammo Box 50 to immediately kill the creature before it can hatch, and destroy the laboratory compound. Ada leaves the burning laboratory to begin her new mission.