"Seraph of the End" 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 a feudal system, enslaving the surviving children in exchange for protection from the virus. The story centers on Yuichiro Hyakuya, a young boy who escapes captivity after witnessing the brutal death of his orphanage family at the hands of the vampires. Driven by a desire for revenge, Yuichiro joins the Japanese Imperial Demon Army, an organization dedicated to eradicating vampires and reclaiming humanity's freedom.

The narrative explores the conflict between humans and vampires, as well as the internal struggles within the Demon Army. Yuichiro, along with his childhood friend Mikaela Hyakuya, who was presumed dead but later revealed to have become a vampire, becomes entangled in a larger conspiracy involving ancient prophecies, demonic powers, and the true nature of the virus. The series delves into themes of loyalty, betrayal, and the moral ambiguity of survival in a fractured world.

Key characters include Yuichiro, whose determination and impulsive nature often put him at odds with his allies; Mikaela, who struggles with his vampiric identity and his bond with Yuichiro; Shinoa Hīragi, a squad leader in the Demon Army who provides strategic support and emotional grounding; and Guren Ichinose, a high-ranking officer with hidden motives tied to the Hīragi family, the ruling faction of the Demon Army. The story also introduces a variety of supporting characters, including other members of Yuichiro's squad and powerful vampire nobles, each contributing to the complex political and supernatural dynamics of the world.

The plot intertwines personal vendettas with larger-scale conflicts, as Yuichiro and his allies uncover secrets about the Seraph of the End, a prophesied being with the power to reshape the world. The series balances action-packed battles with moments of introspection, exploring the characters' motivations and the consequences of their choices. As alliances shift and new threats emerge, the story builds toward a climactic confrontation that challenges the boundaries between humanity and monstrosity.