The game begins on the night of Friday 24 July 1998. The Special Tactics and Rescue Service, a police special forces unit consisting of ex-soldiers and scientists, has been assigned into the Arklay Mountains to investigate a series of cannibalistic homicides conducted by an unidentified group of people. Split into two teams, the "Bravo Team", sent out the previous night, has ceased radio contact, forcing the "Alpha Team" to investigate their disappearance on top of completing the mission.
Alpha Team identifies Bravo Team's derelict helicopter on the ground and investigates, finding the body of its pilot - Kevin Dooley - but no sign of the others, including its co-pilot, Edward Dewey. Soon into the search, Alpha Team's Joseph Frost is attacked by a pack of mutant dogs ("Cerberuses") and his body torn apart. His comrades, unable to save him, are soon forced to flee from the dogs as well. In the commotion, pilot Brad Vickers takes off, stranding the remaining four members of Alpha Team behind. Chris Redfield, Jill Valentine, Barry Burton, and their leader Captain Albert Wesker, PhD. rush into a large mansion seen from afar.
Soon after arriving in the mansion, the four S.T.A.R.S. officers split up to search the building, though it is uncertain which actions are attributed to who. Investigating a gunshot near the dining room, Dr. Kenneth J. Sullivan of Bravo Team is found dying of a fatal throat injury, having been murdered by a mutant cannibal ("Zombie"). Forest Speyer is found on a balcony seemingly dead, but he gets up soon after as another mutant. Richard Aiken is found poisoned from a venomous mutant snake ("Yawn"), and either dies of poisoning or by another mutant after treatment.
Redfield himself discovers Bravo Team's medic, Rebecca Chambers, while exploring the mansion, but she is limited mostly to the medical store rooms to offer treatment for injuries. Valentine meanwhile works with Burton in investigating the mansion, and begins to suspect something is wrong about him due to his movements. As time passes in the investigation, the officers become aware the mansion is part of a base operated by Umbrella Pharmaceuticals and Umbrella USA for viral research, with the escaped mutants being the result of an escaped mutagenic virus which induced a murderous insanity due to brain damage and radical hormonal changes. In further search of the mansion, they learn of the Trevor family - George, Jessica and Lisa - who were abducted by Umbrella Pharmaceuticals in the 1960s for use in research of the Progenitor Virus by one of Umbrella's founders, Dr. Oswell E. Spencer, Earl Spencer, for who the mansion was built for. Lisa is still alive, having been kept as a human test subject for years, though she has been driven mad and horrifically mutated. With the mansion's guards dead or mutated, she is free to roam and kill as she pleases.
In a nearby building used as a dormitory for laboratory workers, it is discovered to be wrecked by a giant plant, "Plant 42". A mutant plant research specimen, it ran amok during the accident and attacked the staff to drain them of blood for sustainable, moving its ivies. Its growth is attributed to drinking from the basement below, which houses a massive shark tank for research on fish-based mutants. In the courtyard's underground, Bravo Team Captain Enrico Marini is discovered injured. He believes there is a traitor within S.T.A.R.S. responsible for their casualties, but is assassinated by a third party who quickly escapes.
Moving into the laboratory, the investigation comes to a close. The nature of the virus research is finally understood to have been part of illegal bio-weapons research on behalf of the United States military in disregard of the Bio Weapons Convention. The latest virus, Epsilon, leaked out during an accident, leading to the staff being infected and, unable to maintain the facility, allowed the bio-weapons to escape. Captain Wesker, a former US Army researcher, is discovered to not only be a former member of Umbrella USA's lab team, but continued to work as a spy for the company throughout. Under orders from Umbrella, Captain Wesker brought S.T.A.R.S. into the mansion to both prevent the alternative of State Troopers being involved as well as to prove the mutants' effectiveness in killing armed professionals. Finally, he has orders to destroy the laboratory to destroy any incriminating material and recover embryonic clone samples of the B.O.W.s. Burton is revealed to have been forced to assist in the destruction of material, under threat of his family's murder. Captain Wesker is cornered on level B4 of the lab, and not only confesses to the actions, but also adds that he plans to betray Umbrella upon completion of the mission, destroying the lab and instead handing over the embryonic clones to a rival company. Umbrella USA's latest bio-weapons creation, the T-002 Tyrant, is awoken from its slumber with orders to kill the other S.T.A.R.S. members. He turns on Captain Wesker instead, and impales him with his claws before going after the others. The laboratory's self-destruct system is activated, and the four remaining S.T.A.R.S. members - Burton, Chambers, Redfield and Valentine - rush to the helipad to alert Vickers to their need of rescue. The T-002 confronts them on the helipad as the helicopter arrives, but is destroyed by a direct hit from a rocket. The S.T.A.R.S. members fly away over the mountains as the Spencer Mansion explodes.