Hope's Peak Academy's unconventional class 77-B is about to have an even more eccentric addition: Chisa Yukizome, an alumna with the title of Super High School-Level Housekeeper—and their new homeroom teacher. Cheerful, passionate, and capable, Chisa immediately sets about correcting the students' problematic behavior and strengthening their relationships. It may not be easy dealing with diverse pupils ranging from princesses and nurses to yakuza and impossibly lucky students, but anything is possible with the power of hope. Meanwhile, Hajime Hinata, an unremarkable boy from the school's Reserve Course, longs for a talent. One day, he has an unexpected meeting with class 77-B's Super High School-Level Gamer Chiaki Nanami, who presents to him a new, hope-filled outlook on life. However, unbeknownst to him, the school's upper echelon is about to execute a sinister project centered around Hajime that will bring Hope's Peak—and the rest of the world—to its knees. Zetsubou-hen chronicles the daily lives carried out at the talent-cultivating academy, and the darkness that lurks beneath. As despair slowly infects hope, plans are put into motion to start the Biggest, Most Awful, Most Tragic Event in Human History, and the end begins.

Kyoutarou Ichikawa may look like a shy and reserved middle school student, but deep within his heart is a bloodthirsty killer. His ultimate desire is to see his classmate Anna Yamada's beautiful face writhing in pain before he ends her life. But this fantasy may never come to fruition, as Ichikawa starts to see an entirely different side to Yamada. Often seeking refuge in the library, Ichikawa frequently runs into Yamada. It is during these encounters that Ichikawa realizes his model classmate is actually an airhead who can never read the room. As they spend more time together, the boy cannot help but feel not only a sense of endearment toward the very girl he wishes to murder but also a desire to protect her at all costs. Is it possible that this sudden change in Ichikawa's perspective could lead to something more?

Yuusuke Yotsuya has always disliked Tokyo, but he especially hates the people who live in it. He would rather thrive in a virtual world than try to get along with those around him. At the end of one school day, he sees the popular athlete Iu Shindou talking to Kusue Hakozaki, who spends less time in school due to illness. But when he looks away from the two and back again, they have seemingly disappeared. Mere moments later, Yotsuya enters a state of free-fall, and the world begins to change around him. Dropping into a large pool of water, the first thing he sees when he comes to his senses is an assortment of enormous monsters. He soon finds out that he has been brought into a game world by Shindou and Hakozaki and that he must complete a quest within 14 days. There is one thing that separates this world from the real world: anyone who dies will be brought back to life in 30 seconds as long as one party member is alive. Tasked with numerous quests that increase in difficulty over time, Yotsuya, Shindou, and Hakozaki attempt to discover the mystery behind the perplexing game world.

Jun Naruse is a chatterbox whose life is colored by fairy tales and happy endings. However, influenced by her deep belief in those tales, she is too naive and trusting, and her words soon shatter her family's bond when she inadvertently reveals her father's affair. Naruse is scarred for life after being blamed for her parent's divorce, and her regrets soon manifest into a fairy egg—a being who seals her mouth from speaking in order to protect everyone's happy ending. Now, even in high school, Naruse's speech remains locked by the fairy egg. Even trying to speak causes her stomach to twist. Though unable to convey her thoughts through words, she is unexpectedly chosen to perform in a musical alongside three other students: Takumi Sakagami, Natsuki Nitou, and Daiki Tasaki. Naruse makes her way to the club room to reject the daunting task, but changes her mind when she overhears Sakagami's beautiful singing. Perhaps the fairy egg curse does not apply to singing, and perhaps Sakagami is the fairy tale prince she has been seeking all along. Will Naruse be able to convey the anthem of her heart?