Set before the events of "Danganronpa: Trigger Happy Havoc," The Despair side of Danganronpa 3 shows the events leading to the rise of the Remnants of Despair and the fall of Hope's Peak and the world into anarchy.
Makoto Naegi, the Ultimate Hope who defeated the Ultimate Despair, Junko Enoshima, is under suspicion of treason against the Future Foundation for harboring the Remnants of Despair who carried on her will. As top members of the Future Foundation, including Makoto's former classmates Kyoko Kirigiri, Aoi Asahina, and Yasuhiro Hagakure, are brought together to decide on Makoto's punishment, they are all imprisoned by Monokuma, the bear avatar of Junko who was thought to have been dead. Monokuma forces everyone to participate in a final killing game, in which they must try to determine a traitor amongst their ranks who will kill them in their sleep, while also trying to avoid being poisoned to death by personalised forbidden actions. Thrust into a game where no one can trust each other, Makoto's ideals of hope are pushed to their very limits.
As Makoto races to stop Ryota from broadcasting his Hope video, he and the others are assisted by the arrival of the 77th Class, who Hajime managed to restore to normal using Izuru's talents. After making their way past a hypnotised task force, Hajime and the others confront Ryota, who blames himself for the entire incident. Feeling that he should not have to carry his burden alone, Hajime and the others ask Ryota to come with them as they aim to atone for their sins, convincing him to cancel the broadcast. Afterwards, Hajime and the others claim responsibility for the killing game, shifting blame from the Future Foundation, before setting off with Ryota towards a new future. Meanwhile, as Kyosuke leaves Makoto in charge of bringing hope to the world as he goes off to shoulder his own burden, it is revealed that Kyoko had managed to survive her poisoning thanks to an antidote that Seiko had made. A few months later, the former Ultimate students get together to rebuild Hope's Peak Academy, with Makoto serving as its headmaster.
Chisa Yukizome begins her job as homeroom teacher for Hope's Peak Academy's 77th Class of Ultmate students. Meanwhile, Hajime Hinata, a student of the school's Reserve Course for students without talent, prepares to undergo an experiment to make him the Ultimate Hope. What follows is a series of tragic events which lead to the birth of the Remnants of Despair and the realisation of "The Biggest, Most Awful, Most Tragic Event in Human History."
