The story begins with our protagonist Konoe Shimatate, the Ultimate Lucky Student, standing outside the gates of Hope's Peak Academy and preparing to enter the marvelous institution of hope. Suddenly, Konoe passes out and soon finds herself inside a classroom where she meets Chisa Komyoin the Ultimate Runner. After recovering, Konoe and Chisa meet the rest of the students who ended up in the same classroom as them. Once everyone's introductions are finished, a mysterious voice calls them to head to the gymnasium for orientation.
They arrive to find the room completely darkened and with a strange smell. Once the lights turn on, the group is horrified to discover that the gym has been splattered with blood everywhere. While everyone is in shock, the iconic love-to-hate mascot Monokuma makes his grand appearance and informs them about their new Killing School Life. Most of the students are in denial that Monokuma is the actual headmaster until the bear summons the hologram of a high school student to appear. Her name is Hold Nova, a state of the art A.I. created for Hope's Peak with the directive of supporting both the students and faculty to the best of her abilities. She then explains the rules of the Killing School Life and how the only way to leave or "graduate" is to kill someone and get away with it. Before she leaves, she informs them that the only way to leave the blood-soaked gym is to accept the terms of the Killing Game. Naturally, no one is willing to accept and claim that none of them will be willing to kill. Except, the mysterious student Tachihaki Hatami accepts the terms leaving the others shocked by his decision. Hold Nova opens the doors and Monokuma takes his leave. When the others question Tachihaki about his resolve, the boy asks his own question to them: "Was anyone among us convinced to commit murder in order to escape?" Everyone is left in disturbed silence while Konoe thinks to herself about the wicked person who trapped them in this deadly game of hope and despair.
After the orientation, Konoe and the others attempt to investigate the school in the hopes of finding any clues or exits that can help them. Sadly, there is nothing that can benefit them which lowers their spirits. The only exit is the giant metal door blocking the entrance that will only be opened once someone commits a successful murder.
The group meets up in the dining hall to discuss what the mastermind is after. Chisa then takes notice of a red wristwatch on her hand. The others notice that they too have wristwatches which are revealed to be E-Handbooks that display their content via virtual screen. While going over the rules, the group goes over how there are more steps and details regarding the "kill to escape" rule. Ryohei Seki, the Ulimate Police Officer, suggests that everyone break into groups so that they can continue to thoroughly explore the school. Chisa and Koin decide to team up alongside Yukime Ryo the Ultimate Calligrapher. The trio make their way to the dorm rooms and discover a weapon kit in the desk. After asking out loud why such a thing is there, Hold Nova appears and explains their function and content. She later reveals that there is a storage room that contains more weapons and other mundane items for the students to use in their daily lives. Once she leaves, the trio continues to explore the other rooms and the storage area where they decide to regroup with the others.While discussing their findings, Konoe brings up the blood filled gym which leads to everyone discussing who the potential survivor is of the previous killing game. Before everyone leaves for the night, Marin Momori, the Ultimate Maid, alo suggests a rule where no one is able to leave their rooms during night time which is deemed acceptable. Four days pass and the group reunites to discuss their situation. Tachihaki begrudgingly tells them to look over the pamphlet for Hope's Peak which results in a discussion over the history of the school. The topics that are discussed involve illegal experiments used to create the Ultimate Hope, the mistreatment of the Reserve Course as a means of extorting money, and the Great Tragedy that followed led by the Remnants of Despair. They also bring up the mastermind responsible for the Tragedy and how they organized their own Killing Game inside Hope's Peak during the Despair Wars. The group then questions how it was possible for them to receive invitations to the school when it was still shut down. Monokuma shows up expressing annoyance at how there hasn't been any murders lately. So he decides to change things up by having the kids watch a video that is downloaded to their E-Handbooks. The video features a blonde newscaster giving a news update on Hope's Peak accepting 15 new students who are completely different from the main group. The video features interviews from several of the students and Konoe discovers her sister among the group. She then makes the connection that several of those students are siblings to the main group, such as Chisa and Ryohei. And what's worse is that they all were part of the previous killing game and were killed in the gymnasium thanks to the mysterious victor. After the video, everyone is in complete shock over the connection. Although the exact details of the previous killing game are unclear as not everyone had family members who attended Hope's Peak at all. Once Monokuma leaves, everyone except Konoe, Yukime and Chisa take their leave while also taking into account Marin's rule to avoid potential murder. Yukime breaks down into tears while Chisa displays a cruel change in attitude. Shaken by the news report and how her brother was a victim of the past killing game, she becomes hostile and antagonistic towards the girls and it escalates to the point where she attacks Konoe with a chair.
The scene then shifts to a flashback of Chisa as a young girl and how she became recognized as a talented runner. She remembers winning a first place trophy while another girl cries that she lost to her. Chisa thinks to herself how she doesn't care much for running but it's the only thing that defines her as a person. We cut to the present where Konoe is unconscious and Chisa says that killing to escape is the only way for her to continue her life as "Chisa Komyoin". The screen fades away and changes to Konoe waking up in her room. Miharu is revealed to have taken her there after her fight with Chisa.
