Plot

The game begins with Leon S Kennedy narrating, overlaying the events in the first three games. He then explains that 6 years after his involvement in the Raccoon city incident, he has been sent on a rescue mission to locate the U.S. president's daughter, Ashley Graham, who has been kidnapped by a mysterious cult. He is escorted to a rural village in an unspecified region of Spain. Upon leaving the vehicle, he begins questioning the villagers but is attacked by an infected villager with an ax. After killing the villager in self defense, he sees the police who escorted him there fleeing as a mob of villagers swarm around Leon. The Villagers were simply normal farm people who became driven insane by a virus and pledge their lives to Los Illuminados. The virus within them is a mind-controlling parasite known as Los Plagas. The villagers swarm around Leon and prepare to kill him, shortly after he sees that they have killed and are currently roasting one of the officers who brought him there. Just then, Ada Wong appears in another part of town and rings the bell of the church, arresting the attention of all the infected villagers. The villagers abandon Leon and walk into the church, leaving the confused Leon to wonder what has caused their shift in attitude. The title "Resident Evil 4" appears on screen.

Leon is attacked by the villagers once again when they attempt to crush him with large boulders. He escapes and finds an abandoned building where he begins freeing a captive named Luis Sera. However, more infected villagers appear being led by what Luis calls "The Big Cheese", Bitorez Mendez. Leon attacks the giant leader, but is easily subdued. He is injected with Los Plagas while unconscious and awakens, tied to the floor back-to-back with Luis. The two quickly befriend each other, realizing they were both police officers and have a bit in common. An infected villager wielding an ax attacks them mindlessly and inadvertently frees them. The two split up soon after and Leon locates Ashley in a church by Luis' information. He contacts new special agent Ingrid Hannigan several times and the two discuss courses of action. Leon and Ashley escape the church after encountering the cult leader Osmond Saddler, who reveals his plan to infect the president after she returns home to the white house, explaining to Leon and Ashley that he has injected them both with Los Plagas.

Leon is attacked by Mendez and nearly killed twice, only for Mendez to let him off with a warning upon seeing that he is infected, and being distracted by Ada on the second occasion. Leon however manages to kill Mendez in a barn while Mendez begins transforming into an abomination. Leon and Ashley are then chased into a Gothic castle where they take refuge, only to be attacked by the midget henchman of Saddler, Ramon Salazar. Leon immediately takes a disliking for Salazar and both he and Ashley are separated by Salazar's traps. Luis returns and is about to give Leon a vaccine for his and Ashley's condition, only to be impaled by Saddler who strips him of the vaccine and tells Leon that he will be joining them soon. Saddler leaves and Leon tries to help the dying Luis, who explains to Leon that he was a former chemist for Saddler before changing his ways. He gives Leon a tube of pills that will slow the effects of the virus before dying. Leon mourns the death of his mutual friend and continues looking for Ashley. After killing countless of Salazar's henchmen, Leon makes his way back to Ashley and rescues her.

Leon bumps into Ada who still cares for Leon since his rescuing of her throughout the events of "Resident Evil 2", despite him accusing her of working for Albert Wesker. However, Ashley is captured again and brought to another island. Leon confronts and kills Salazar along with his bodyguard who mutate to hideous beasts. Leon then is aided by Ada who drives him to the island via a motorboat before separating from him. Leon searches the island, and then discovers that a former partner of his, Jack Krauser, who he believed to have died in a helicopter crash prior, has turned his back on Leon and works for Saddler. He also runs into Krauser and the two engage in a knife fight when Krauser confesses that he kidnapped the president's daughter. Krauser is about to kill Leon but Ada intervenes, and Krauser escapes.

It is revealed that both Krauser and Ada are working for Wesker, but Krauser has higher ambitions, and Ada aids Leon. Both want to secure a Plagas sample for Wesker though Krauser works as a double agent for Saddler. Losing trust in Krauser's loyalty, Saddler orders Krauser to kill Leon, and after a vicious battle, Leon gains the upper hand and shoots Krauser to death. Saddler contacts Leon and congratulates him, telling Leon that soon Leon will take Krauser's place as his bodyguard, only for Leon to rebuff him. Leon asks STARS for backup and they send his friend Mike in an armed helicopter. The two kill many of Saddler's men before Saddler kills Mike via a bazooka. Leon grieves his friend Mike and swears vengeance upon Saddler. Leon breaks into the facility, killing many monsters and finally rescuing Ashley where they escape by jumping down a disposal shaft. However, Saddler appears and controls the parasite in both of them, by incapacitating Leon and forcing Ashley to come with him. Leon watches helplessly as Ashley leaves with the monster.

Ada comes to help Leon, but his virus begins taking control and attempts to strangle her. Ada brings him to his senses by stabbing him in the leg and awakening him. Leon apologizes, and Ada agrees to help him find Ashley. Leon rescues Ashley, held up in a captivity tube when Saddler attacks. Ada distracts him with sub-machine gun fire. Ashley and Leon escape and the two extract the Las Plagas parasite from each other via a specialized radio therapeutic device. Leon and Ashley are about to leave the island, but Leon notices that Ada is in trouble. He orders Ashley to wait for him outside a iron plant site on the island, before rushing back. He rescues Ada who is being held captive by Saddler who approaches and explains that all mankind is doomed to his power. Saddler transforms into a hideous twisted abomination and after an intense struggle, both Ada and Leon manage to kill Saddler, setting the island to destroy itself.

Leon reunites with Ashley and the two escape via a jet ski as the island explodes into an inferno of fire and smoke. Ashley offers to thank him via "overtime" when they get home, only for Leon to politely refuse. Ashley asks him who Ada is and he replies that Ada is a part of him that recurs from time to time as they drive off into the sunrise. The end credits roll while showing old sketches of how the village became infected with the Los Plagas via Saddler's manipulations. After the credits are finished, there is a humorous post credit scene in which Ingrid Hannigan reconnects with Leon to ask him on the whereabouts of the mission, the communication having been lost earlier. He comments of how cute she looks without her glasses, only for her to rebuff his charm, much to his increasing delight.