"High School of the Dead" is set in a world where a sudden and unexplained pandemic turns the majority of the population into aggressive, flesh-eating zombies. The story begins at Fujimi High School, where a group of students and staff find themselves trapped as the outbreak rapidly spreads. Among the survivors are Takashi Komuro, a resourceful and determined student; Rei Miyamoto, Takashi's childhood friend and skilled kendo practitioner; Saeko Busujima, the disciplined and highly capable kendo club captain; Saya Takagi, a sharp and pragmatic class representative; Kohta Hirano, a timid but skilled marksman; and Shizuka Marikawa, the school nurse with a compassionate demeanor. Together, they navigate the chaos of the zombie apocalypse, struggling to survive while searching for safety and answers.

The group faces numerous challenges, including the constant threat of the undead, dwindling resources, and the moral dilemmas of survival. As they venture beyond the school, they encounter other survivors, some of whom pose as much danger as the zombies themselves. The narrative explores themes of trust, leadership, and the fragility of societal norms in the face of catastrophe. The characters' relationships evolve under the pressure of their circumstances, with tensions and alliances forming as they confront both external threats and internal conflicts.

The series balances intense action sequences with moments of character development, showcasing the group's efforts to adapt to their new reality. Their journey takes them through urban landscapes overrun by zombies, abandoned military installations, and other survivors' makeshift strongholds. Along the way, they uncover fragments of information about the outbreak's origins, though the full picture remains elusive. The story concludes on an open-ended note, leaving the characters' ultimate fate unresolved as they continue their struggle for survival in a world teetering on the brink of collapse.