"Seraph of the End: Vampire Reign" is set in a post-apocalyptic world where a mysterious virus has wiped out most of humanity, sparing only children under the age of 13. In the aftermath, vampires emerge from the shadows and establish dominion over the surviving human population, using them as livestock for blood. The story centers on Yuichiro Hyakuya, a young boy who escapes from a vampire-controlled orphanage after witnessing the death of his fellow orphans, including his close friend Mikaela Hyakuya. Yuichiro vows to avenge his comrades and eradicate the vampires.

Years later, Yuichiro joins the Japanese Imperial Demon Army, an organization dedicated to combating the vampire threat and reclaiming humanity's freedom. The army employs cursed gear—weapons imbued with demonic power—to fight the vampires. Yuichiro, driven by his hatred for vampires and his desire for revenge, becomes a skilled soldier. However, his journey is complicated by the revelation that Mikaela, whom he believed to be dead, has been turned into a vampire and now serves the enemy. This discovery forces Yuichiro to confront his feelings of loyalty, vengeance, and the blurred lines between humanity and monstrosity.

The narrative explores themes of survival, identity, and the moral complexities of war. Key characters include Shinoa Hīragi, Yuichiro's squad leader, who provides strategic guidance and emotional support; Yoichi Saotome, a compassionate and skilled archer; and Mitsuba Sangū, a determined and prideful soldier. The vampires, led by figures such as Ferid Bathory and Crowley Eusford, are portrayed as both antagonists and complex beings with their own motivations and hierarchies.

As the story progresses, it delves into the origins of the virus, the true nature of the demons powering the cursed gear, and the ancient conflicts between humans, vampires, and seraphs—mythical beings tied to the world's destruction. Yuichiro's journey becomes increasingly intertwined with these larger mysteries, revealing his own connection to the seraphs and the potential role he may play in shaping the future of both humans and vampires. The series balances intense action sequences with moments of introspection, creating a layered narrative that examines the cost of survival and the meaning of humanity in a fractured world.