At Hope's Peak Academy, an elite school for "Ultimate" students, 16 teenagers have gathered together to begin their new year. However, once they set foot inside, they all promptly pass out and awaken later in a classroom. A pink and white bunny named Usami appears and informs the students that they will be going on a school trip to an island, and that they can leave once they become good friends with one another.

However, their fun in the sun is quickly interrupted by a black and white bear named Monokuma. He overpowers Usami and introduces himself as the students' headmaster, revealing that they are on a "School Killing Trip": if they want to leave, they have to kill one of their classmates without being caught. When the first body is discovered, Nagito Komaeda, the "Ultimate Lucky Student," strongly believes that none of them could be capable of murder. However, with so much at stake, even Komaeda's feelings of hope may be overridden with despair.

The series has been licensed in English as Danganronpa 2: Ultimate Luck and Hope and Despair by Dark Horse Comics.