Highschool of the Dead is set in present-day Japan, beginning as the world is struck by a deadly pandemic that turns humans into zombies, euphemistically referred to by the main characters as "Them").

The story follows a group of high school students (and the school's nurse) as they deal with a worldwide catastrophic event known as the "Outbreak". As the cast tries to survive the zombie apocalypse, they must also face the additional threats of societal collapse, in the form of dangerous fellow survivors, and the possible decay of their own moral codes. Starting from the high school, the students escape into town where they must deal with a corrupt teacher and his students. They check their homes for survivors, and pick up a little girl and a dog. Later, they hold up at a mall, travel through a police station, and eventually make their way to an elementary school that is supposedly a safe zone.