A year can change a person's life forever. The 365 days Class 3-E of Kunugigaoka Junior High spent with their eccentric teacher, Koro-sensei, certainly did. Carrying the memories of that year close to their hearts, alumni Nagisa Shiota and Karma Akabane return to their former classroom to recall the events of that momentous time of their lives. Nagisa and Karma are reminded by the familiar rooms, desks, chalkboard, and the class album of the events that shaped them into assassins and prepared them for the real world. That is the legacy of their octopus-like teacher—who had introduced himself by threatening to destroy the world if they didn't kill him by the end of the school year—and the time spent in the bizarre yet exceptional Assassination Classroom.

Spirits have always been attracted to Keitarou Gentouga due to his strong spiritual presence. A traumatic encounter with one had caused his right hand to be cursed, forcing him to wear a glove at all times. Now a college freshman, Keitarou is trying to live as normal a life as possible. With the encouragement of his childhood friend Eiko Houzuki, he becomes a private tutor. Since he is at the top of his intake class, his first client is the tutoring firm's most promising student, Yayoi Houzuki. To Keitarou's surprise, Yayoi is Eiko's cousin, and she possesses two pupils in each eye—allowing her to see into the spirit world and purposely seek vengeful spirits to exorcise. Ever since a car accident killed both her parents, Yayoi has been searching for the powerful spirit that kidnapped her mother's departed soul. Seeing that spirits are so attracted to Keitarou, she ropes him into helping her collect other evil spirits that will assist in her future fight. Although her quest is dangerous, Keitarou reluctantly decides to join her, even as each new spirit they meet has him questioning his resolve at every turn.

High school student Haruka has always been a content loner. One day, he and his class are abruptly transported to another world and given skill points to use when choosing from an assortment of abilities and magical powers. Unfortunately, Haruka arrives last, and he can only use his points on the seemingly impractical abilities the others had no interest in. Although he is on his own again and must adjust to his new life by himself, he much prefers it that way. However, Haruka's peaceful solitude is short-lived, as he runs into some of his classmates. Weak to their pleas for help, he ends up sheltering and helping them reunite with the others. But the different cliques struggle to see eye to eye, forcing Haruka to find a way to end the infighting and restore harmony between them to survive the unfamiliar world.

As dungeon-like treasure vaults started appearing throughout the land, more and more people began signing up as treasure hunters—risking their lives to obtain the vast riches and ancient relics inside. In the imperial capital of Zebrudia, the top hunter party is the Grieving Souls—a group of six childhood friends led by Krai Andrey, who is thought to be the strongest of them due to having a reputed wide array of skills. However, Krai actually has no special talent. His accomplishments are actually the result of his friends being overpowered. Krai has repeatedly attempted to leave the party out of fear his lack of aptitudes would one day cause his companions' downfall. Nevertheless, everyone around Krai thinks differently, making him feel obligated to remain the group's leader.