The story begins in June, 2013, where President Adam Benford arrives at Ivy University in Tall Oaks to make a speech regarding bioterrorism, at which he intended to publically-release classified information regarding US-involvement in the Raccoon City Destruction Incident nearly fifteen years prior. During his visit, bioterrorists strike the university, with a Lepotica releasing a vapour cloud of C-Virus into the university's ventilation, infecting a large number of people. Leon S. Kennedy of the newly formed Division of Security Operations - an America-centric anti-bioterrorism organization separate from the BSAA - comes to the President's aid, though finds him already as a zombie, consuming the body of a recent victim. Getting up and preparing to eat one of his Secret Service agents, Helena Harper, Leon is forced to shoot his friend. Helena's acceptance of blame for the President's death makes Leon suspicious. Through Helena's call with Ingrid Hannigan, Leon announces the President's death, and is properly-introduced to Helena, who claims that the two of them have found a lead at the nearby church. Willing to work with her, despite her prior suspicions, Leon also lies about the lead to Hannigan. Leon and Helena work together to escape the zombie-infested campus and town to the aforementioned church, bringing some of the outbreak's survivors with them.
Ivy University: a historic school nestled in the center of the city of Tall Oaks. This innocuous setting soon changes beyond recognition when it becomes the epicenter of a bioterrorist attack.
Unleashed indiscriminately onto the populace, the virus mutates all who are infected into literal walking-corpses. In a matter of minutes, the school and surrounding city are transformed into a nightmarish hell.
President Adam Benford, who was at the school intending to publicly reveal the truth behind the Raccoon City Incident, is among the infected. Now an inhuman monster, the president joins the carnage and begins feasting on human flesh.
Agents Helena Harper and Leon Kennedy rush to the president's side. Leon in particular was close to the president, having fought together to eradicate B.O.W.s (bio-weapons) and put an end to bioterrorism.
Now, faced with the creature before him, Leon is forced to make the most cruel of choices, and he shoots his comrade and commander, the president.
With the gravity of their situation just starting to settle in, Helena makes a shocking revelation: she claims that she was responsible for this tragedy. Furthermore, she promises to disclose the whole of the truth behind the attack, but only once she and Leon make it to the Tall Oaks Cathedral.
Leaving this gruesome scene, they make their desperate escape from the university. Next, overcoming the bedlam that has engulfed the city of Tall Oaks, the pair are narrowly able to get a hold of a bus, and head to the cathedral.
After fighting through hordes of the infected, Leon and Helena somehow manage to reach the cathedral.
Below the hallowed grounds is a strange lab, dotted with cocoon-like entities that seem to have mutated from humans. Here, Leon views a mysterious tape of the spy Ada Wong being birthed from a cocoon.
However, the "truth" of which Helena had spoke is buried even further in the depths: in the deepest recesses of the catacombs is Deborah, Helena's sister. What should have been a joyful reunion, however, is cut short in mere moments as Deborah suddenly begins to burn and writhe in agony.
She transforms into a cocoon like the ones seen in the lab. However, this is followed by a second transformation, as Deborah emerges from the chrysalid, no longer herself, but as a monstrous B.O.W. that proceeds to attack Leon and Helena. As the ensuing battle grows more dire, Ada suddenly comes to the two agents' rescue. Her appearance gives Leon pause as he recalls what he had seen in the lab, sparking feelings of distrust.
The fight, however, is ended by Helena. Choking back bitter tears, she is forced to kill her sister, the very person she had come to rescue. With her sister lost forever, Helena finally reveals the truth of what happened in Tall Oaks.
The person behind it all was a single man: Derek Simmons, a presidential aide. Helena goes on to explain that her sister Deborah had been taken hostage by Simmons, forcing Helena to assist in his plan to assassinate the president. With this, Ada takes her leave, and the two agents attempt to contact federal agent Hunnigan; however, it is Simmons who answers their call.
Derek Simmons was the man who orchestrated the attack in Tall Oaks, which lead to the assassination of the president. As part of his plan, Simmons frames Leon and Helena for the crime, taunting them with the promise to clear their names if they come to him.
Having been used by Simmons, and ultimately losing her sister to his treachery, Helena is pushed to the brink.
With the two agents now sharing a common enemy, they vow to bring Simmons to justice, and begin to make their way out of the catacombs.
However, upon arriving at the surface, Leon and Helena bear witness to yet another tragedy: in what must be an attempt to contain the outbreak, Tall Oaks is eradicated by missile strike. Suffering the same fate as Raccoon City, the once picturesque city is wiped off the map.
Elsewhere, we find Simmons on his way to China, where by no small coincidence, a similar bioterror attack has begun.
Prime suspects in the assassination of the president, Leon and Helena, enlist Hunnigan's help in faking their own deaths, and then follow Simmons to China.
When Leon and Helena at last arrive in China, they find panic in the streets as a bioterror attack is in full-swing.
Amidst the chaos, however, Leon is reunited with fellow Raccoon City Incident-survivor Sherry Birkin. Now a federal agent, her current assignment is to protect Jake, the young man with her. It turns out, however, that Sherry's superior is none other than Simmons.
Taken aback by Simmons' actions, Sherry reveals his location to Leon. Despite being separated in the ensuing fight, Leon promises to meet up with her again at Simmons' location.
On their way there, Leon and Helena catch sight of Ada, and attempt to get information out of her. However, at that very moment Chris of the BSAA shows up and, in a rage, accuses Ada of being the mastermind behind the attacks. Leon interjects, insisting that the real culprit is Simmons; as their argument reaches a boiling point guns are drawn, giving Ada an opportunity to escape. Leaving her capture to Chris and company, Leon and Helena head after Simmons.
The two agents arrive to face off with Simmons just ahead of Sherry and Jake. Determined to settle this very personal vendetta themselves, Leon and Helena make cover for the younger pair to escape, then proceed to attack.
However, Simmons is injected with the C-Virus, endowing him with unspeakably powerful mutative abilities; a fierce battle ensues, with Leon and Helena narrowly putting an end to him.
Simmons is defeated, and retribution for the deaths of President Benford, Deborah and countless others is had.
Just as the two agents begin to breathe a sigh of relief, they receive a transmission from Chris telling them to immediately escape the city. Looking to the sky reveals that it is already too late, as a missile explodes overhead,releasing gas that engulfs the city.
It seems to the agents as if all hope is lost, as a tragedy greater than even Raccoon City or Tall Oaks unfolds before their eyes.
Desperate but determined to escape, U.S. agents Leon Kennedy and Helena Harper soldier onward through the streets of China; the city around them now pandemonium, overflowing with the walking dead.
Facing the most grave of circumstances, Leon vows to survive this tragedy for the sake of comrades and friends that did not. However, as the night drags on, hope dwindles; it seems that dawn will not come. Rescue comes in the form of a lone helicopter, whose pilot is none other than Ada Wong.
Ada, who Chris had reported dead.
Riding in Ada's helicopter, the two agents head to the roof of the Quad Tower. There, they find Simmons. Enraged at the sight of the three of them and powered by the enhanced C-Virus, Simmons proceeds to attack—his body undergoing mutation after mutation.
Following a grueling battle, and with Ada's help, Leon and Helena at last are able to defeat Simmons for good. They then go to make their escape via the helicopter, though Ada is nowhere in sight.
Having received evidence of Simmons' wrong doing from Ada, Leon takes flight while still pondering where the spy had gone.
- ↑ Despair that is repeated (繰り返される絶望 Kurikaesareru zetsubō )