Kivotos is a federal megalopolis comprising thousands of schools and is led by the General Student Council (GSC), which acts as its governing body. Ironically, despite being an academy city, Kivotos is rife with gun violence, and all students wield firearms as part of their everyday lives. As if the crisis in Kivotos was not enough, the GSC president is nowhere to be found. Fortunately, before her sudden disappearance, the GSC president enlisted the help of Sensei—a teacher who is most likely the only one in Kivotos—to support students in their time of need. Sensei's first course of action is to assist Abydos High School, a once prestigious academy now with merely five students in attendance. These remaining students are doing everything they can to pay their academy's crippling debt of almost one billion yen.

On live television, Mina Tepes, the ruler of all vampires, reveals the existence of her species to the world and states her plan to build a sanctuary in Japan for vampires, called the Vampire Bund. Using her family's wealth to pay off the nation's debt, they have agreed to let her build this safe-haven for her fellow creatures of the night. But not everyone is so easily swayed by Mina's influence, as her announcement brings about conflict with humans who believe that the queen's quest for peace is a façade. Akira Kaburagi does not believe in vampires and gets uneasy whenever they are brought up, although he has yet to realize why. Apart from suffering a head injury a year ago, he lives on blissfully until he meets Mina. She triggers within him memories of a life he had long forgotten, and he soon begins protecting her without understanding why. But Akira's secret is far stranger than he could have ever thought possible—he discovers that he is a werewolf, sworn from birth to protect the vampire queen, even if it costs him his life. Now, as these two dance a rondo of death in the Vampire Bund, Mina and Akira find out just how deep their bond goes.

The second season of Strike the Blood which adapts three arcs from the 9th, 11th, and 12th light novel volumes.

The anime will depict the lively everyday lives of the demon brothers through special episodes separate from the game’s main story (Lessons).