Makoto Naegi, an average student, enrols at the prestigious Kibōgamine Academy for talented students. However, the moment Makoto steps inside the school grounds, he falls unconscious and wakes up in a dorm room littered with security cameras and steel plates. Following a note's instruction to assemble in the gym, Makoto finds 14 other unique students in a similar situation, including a school idol from his old middle school, Sayaka Maizono. It is at this point that the self-proclaimed principal, a stuffed bear named Monokuma, appears, announcing that the students will be staying in the school for the rest of their lives, with only those who kill another student being able to leave. The students spend the next few days searching the school grounds in order to try and find an alternative exit. When Monokuma notices noone has any particular motive to kill anyone, he shows each student a personalised DVD motivating them to escape.

As Makoto tries to grow accustomed to the situation, he learns from Monokuma about the faulty door on his shower room. Afterwards, Sayaka comes to Makoto's room, saying she is afraid that someone may be after her, so Makoto offers to switch rooms with her to put her at ease. The next day, however, Makoto discovers his room in a mess and is horrified to find Sayaka lying dead in the shower room, having been stabbed in the stomach with a kitchen knife. As Makoto becomes angered by this tragic turn of events, Monokuma explains that one of the students is responsible for her murder and they must judge for themselves who the killer is in a "class trial". If the guilty culprit is successfully deduced, that person will be executed, but if they accuse the wrong person, then the culprit will get to escape the academy whilst everyone else will be put to death.