D.S.O. agent Leon S. Kennedy is on a mission to rescue Dr. Antonio Taylor from kidnappers in San Francisco, but his pursuit is thwarted by a mysterious woman. Simultaneously, B.S.A.A. agent Chris Redfield investigates a series of zombie attacks in the same city, where the infection's source cannot be identified. The only link between the victims is that they all recently visited the infamous prison island of Alcatraz. Claire Redfield, following her own lead on a killer whale infected with a strange virus in the bay, and Jill Valentine, are drawn into the same mystery.

The manga opens with a flashback to the 1998 Raccoon City incident, revealing the origin of the main antagonist, Dylan Blake. As a young operative for Umbrella, Dylan was forced to kill his own infected comrades, including his friend JJ, under orders to quarantine and eliminate all personnel. Years later in 2015, Dylan has allied with Maria Gomez, a criminal seeking revenge, and now holds Dr. Taylor captive. He unleashes a new, advanced strain of the T-virus on Alcatraz using mosquito-like drones, turning the island into a horrific battlefield.

Following the clues, Chris, Jill, and Claire travel to Alcatraz posing as tourists, but are quickly caught in a sudden zombie outbreak. On the island, they reunite with Leon, who has been infiltrating the location on his own mission. The group, which also includes B.S.A.A. advisor Rebecca Chambers, discovers that Dylan is using Taylor's technology to weaponize the virus. After being captured and infected by Dylan, the team is saved by Rebecca, who develops a vaccine. The narrative culminates in a final confrontation where Dylan merges himself with a powerful bio-organic weapon. With the combined efforts of Chris, Leon, Jill, Claire, and Rebecca, they manage to defeat him and escape the nightmare of Alcatraz.