The students of Class 3-E have a mission: kill their teacher before graduation. He has already destroyed the moon, and has promised to destroy the Earth if he can not be killed within a year. But how can this class of misfits kill a tentacled monster, capable of reaching Mach 20 speed, who may be the best teacher any of them have ever had?

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.