Fuyuhiko has been trapped in the execution procedure by mistake and needs emergency aid--that means that, due to school rules, his rival Monokuma has to save his life, but Monokuma decides to make evil lemonade out of these lemons and use the medical theme for his next murder motive: the Despair Disease. Students who catch it find their personalities changing dramatically, causing confusion and chaos.

A new group of students enroll at Hope's Peak Academy, but this time they find that class is being held on a remote tropical island with no escape. They soon learn the only way to get off the island is to kill a fellow student and get away with it after a class trial.