It is early 2011, and US federal agent Leon S. Kennedy has had his vacation time interrupted to be sent into the country, where he is to link-up with a CIA agent under the codename of "Scarecrow", who may have information regarding the bioterrorists. Unfortunately for Leon, the US was ordered to pull-out soon after his arrival. Angered by his ruined vacation time and by the US' lack of commitment, Leon goes rogue, still seeking out Scarecrow. In an underground parking garage, he stumbles onto the CIA operative, who has been badly wounded. Managing to exclaim the word "Beekeeper", which Leon ascertained to be the bioterrorists' connection with a nearby honey truck, a Licker attacks and kills the agent. Escaping from its initial onslaught, Leon is forced down by an explosion and soon after loses conciousnes when he sees a man command the Licker in not killing Leon. Coming to, he finds himself in the basement of a house under search from the Eastern Slav army, while being interrogated by one of the rebels, JD, who is in the room alongside Alexander Kozachenko ("Buddy") and Ivan Judanovich ("Ataman"). Noticing that Judanovich is beginning to convulse heavily, Leon suspects that he may be on his way towards transforming into a zombie, and advises JD to keep an eye on him. Searching the building again, the soldiers realize that someone is hiding underground and begin to open fire. JD is hit on the way out and believes he is dying only to later find out the vest he took from Leon was the one that saved him, while Ataman is so weak that he has to be carried by Buddy. Heading through underground tunnels, Ataman becomes too weak and elects himself to be killed, knowing what will happen to him soon if Buddy does not do it. He is shot twice in the head, killing him. Buddy, taking over as leader of the group, orders JD to hide while he heads off to the surface. Following JD, Leon discovers that the Plaga parasites were being used by the rebels, which unexpectedly - for the rebels, at least - led to some of their men turning into savage beasts, with at least one of the members being found by Leon impaled on an axe. Finding that JD is hiding from one of the hosts, he chooses to work with him in taking out the mutual threat. However, he finds he must kill the host on his own, as JD - despite his tough-guy attitude during the interrogation - is unprepared to kill people he grew up with, or even people in general.
The President of the Eastern Slav Republic Svetlana brings in Ada Wong to provide her information on the plaga's that are being used by the Eastern Slav Army. Svetlana later realises that Ada is using a guise as a BSAA agent and tries to figure out as to why she is here.
Outside of the Presidential Palace, Kozachenko continues his planned attack on the building, having become the host of a Dominant Species Plaga. Sending out an army of Lickers, the soldiers guarding the perimeter were quickly-eradicated, allowing Leon to sneak in, though still not an ally of Kozachenko. Making his way down to an underground facility, Leon and an escaped-Ada confirm that Svetlana was behind the terrorist attacks in her own country, using the secessionist movement for political gain and then killing them off to remove witnesses. At this point, Kozachenko and his Licker army attack the facility, quickly killing off the remaining soldiers with only Svetlana and her personal secretary surviving, having retreated behind shatter-proof glass. With the two of them safe Svetlana releases two of her Tyrants - a modified derivation of the T-103 line - to dispose of Leon and Kozachenko. Eventually Leon and Kozachenko escape from the compound, losing the Tyrants in the process when their elevator collapses from the sheer weight of the two. Reaching the top, they are unfortunate in encountering a third Tyrant, designated "013". By using the remains of his Licker army, Kozachenko outwit the Tyrant into damaging an oil tanker, allowing Leon to use it as fuel for an explosion. What isn't put into perspective is the nature of the power limiter - with its limiter damaged, "013" mutates into its Super Tyrant form, where it proceeds to seek out Leon, who escapes solely because of a tank ramming into "013". In a stalemate between the vehicle and monster, Leon takes control of the turret, trying to get a good shot to fire at the Tyrant but is unable to aim because its head is blocking the path of the cannon. Another of Kozachenko's Lickers' attacks the creature, allowing it to get into the range of the turret, which proceeds to completely destroy its head when fired. The celebrations are short-lived when the other two of Svetlana's Tyrants finally reach the ground floor, having also become Super Tyrants. Ready to kill Leon and Kozachenko, two aircraft make a sudden appearance and destroy the creatures.
With the Tyrants defeated, Leon realizes that the US has been monitoring Leon the whole time - Leon being a personal friend of President Adam Benford. It is revealed soon after that both the United States and Russian Federation, forgetting their tense rivalry over Eastern European relations, take joint-action in intervening in the war when Svetlana's role as a supporter of terrorism is revealed. In their joint-invasion, the remnants of the Eastern Slav army are made Prisoners of War for their association with a terrorist state.
As Leon watches the U.S. and Russian forces march on the republic to overthrow its government, Buddy wonders if Leon was aware of both countries' involvement from the start. Beginning to feel more overwhelmed by how events transpired and where he was currently, Buddy becomes hopeless. Showing deep regret over the loss of his mentor, Ataman, and his friends, Buddy proclaims he has nothing more to fight for, and begs Leon to kill him before he turns into a monster. When Leon fails to respond, Buddy draws his pistol as part of a suicide attempt to free him of the horror he saw with the Plagas. Leon denies him the right to die and confiscates Buddy's handgun, scolding him in the process, telling Buddy that he owes it to the people who died to continue living, even if it means being paralyzed for the rest of his life, Leon proceeds to shoot Buddy to kill the Plaga attached to his spinal cord, so he can live without becoming a monster.
In the aftermath of events, Buddy remains in Eastern Slav. He watches as children run by happily up a cobbled street as he wheels himself along in a wheelchair, a canteen Leon gave to him still on his person. Stopping briefly, Buddy watches as children run by on their way to the school ahead. Smiling, he continued to wheel himself uphill and towards the building implying that he has resumed his previous occupation as a school teacher.