D.S.O. agent Leon S. Kennedy is on a mission to rescue Dr. Antonio Taylor from kidnappers, when a mysterious woman thwarts his pursuit. Meanwhile, B.S.A.A. agent Chris Redfield is investigating a zombie outbreak in San Francisco, where the cause of the infection cannot be identified. The only thing the victims have in common is that they all visited Alcatraz Island recently. Following that clue, Chris and his team head to the island, where a new horror awaits them.

The anime takes place in 2006, and centers on Akio Hoshigami, who due to a leg injury is forced to give up on her dream of being a track-and-field star. Akio and her friend Ayano Umisoe move on to high school together. Amidst new activities and meeting new friends, Akio gradually starts acting like herself again. Then one day Ayano suddenly disappears.

Featuring stories from the manga not adapted in the main anime.