Danganronpa takes place at an elite high school called Hope's Peak Academy, which accepts talented "Super High School Level" students of the highest caliber in various fields each year, along with one average "Lucky Student" who is selected by raffle. Makoto Naegi, a fairly optimistic but otherwise average student, is chosen as one of these students. However, when Makoto arrives outside of the gates of the Academy, he loses consciousness and wakes up inside the school, where he meets fourteen other newly picked Super High School students who are in the same situation as him. It is there that a sadistic, remote-controlled, monochrome bear named Monokuma appears before them, telling them they will be imprisoned in the academy for the rest of their lives. He offers only one way for students to graduate from the academy: murder another student and get away with it.
When a murder occurs, a "class trial" is held, in which the remaining students must determine amongst themselves who the killer is. If the students can successfully determine the true culprit, that person is put to a gruesome and ironic execution for disrupting school order. However, if the wrong accusation is made, then the true killer will be allowed to leave the academy whilst everyone else will be put to death. In a place where anyone could be a victim, everyone is a suspect and no one can be trusted, it is up to Makoto to survive these class trials and solve the true mysteries of Hope's Peak Academy.
As the game progresses, several students are killed, forcing the remaining students to figure out the killers. During the investigations, Makoto receives assistance from Kyouko Kirigiri, a mysterious girl with no recollection of her past, but possessing keen observational and deductive skills. Using his own investigative skills, Makoto manages to figure out the culprit in each killing. However, through their investigations, it becomes clear to the remaining students that regardless of what they do, Monokuma has no intention of letting them leave the academy. The surviving students band together to work against Monokuma, and find out the true mastermind behind the death game is Junko Enoshima, one of the students previously thought killed, but had, in fact, employed her identical twin sister, Mukuro Ikusaba, to impersonate her, only to ultimately kill her on a whim.
Junko reveals that the students all had already been in the academy for two years and all knew each other. However, when an unspecified apocalyptic event, caused by a mysterious movement calling themselves "Super High School Level Despair", led global society to collapse and violent anarchy erupted world-wide, the students and the headmaster agreed to barricade themselves inside the academy to wait out the crisis. Unfortunately, Junko, herself a secret member of and the implied leader of Super High School Level Despair, then murdered the headmaster, took control of the academy, and erased all of the students' memories of having known each other. Her motivation is to spread further despair all over the world by televising the world's brightest and most talented students murdering each other. Having been found out and her plans foiled, Junko then commits suicide by subjecting herself to a combination of all of the executions she used to kill the past culprits.
Afterwards, Makoto, Kyouko, and the surviving students exit the academy, uncertain of the current state of the world.