A class of junior high "misfit" students who are tasked with assassinating their new teacher, an octopus-like creature nicknamed Koro-sensei, who destroyed the moon and threatens to destroy Earth in a year. The students have to learn to balance their assassination attempts with the lessons from Koro-sensei, who is surprisingly an excellent teacher, while the government offers a ¥10 billion reward for his head. Each episode often focuses on individual students, their growth, and their internal conflicts between wanting to kill their teacher and growing to care for him.

Class 3E and while some things have changed, the class assignment is still the same: kill their teacher before the end of the year. Easier said than done since Koro Sensei's made it clear he won't go down without a fight.