A perpetually suicidal teacher attempts to find meaning in a world that constantly disappoints him. Nozomu Itoshiki, a teacher who sees only despair in life, tries to end his life in various ways, only to be thwarted by his students or circumstances. His students, each with their own peculiar personalities and obsessions, often misinterpret his despair as something else entirely, leading to absurd and darkly comedic situations. The narrative framework is that of a gag manga, with each chapter presenting a self-contained, often surreal, scenario that highlights the characters' eccentricities and the bleakness of modern society.

Sayonara, Zetsubou-Sensei is widely recognized for its unique brand of dark humor and sharp social satire. Critics and readers often praise its clever wordplay and the way it tackles bleak themes with absurdity. The series is noted for its distinctive art style and its willingness to push boundaries in its comedic approach. While its humor can be niche and its themes challenging, it has garnered a dedicated following for its intellectual wit and unconventional narrative.