Ohana Matsumae is an energetic and wild teenager residing in Tokyo with her carefree single mother. Abruptly, her mother decides to run away with her new boyfriend from debt collectors, forcing the young girl to fend for herself—as per her mother's rely only on yourself philosophy—in rural Japan, where her cold grandmother runs a small inn. Driven to adapt to the tranquil lifestyle of the countryside, Ohana experiences and deals with the challenges of working as a maid, as well as meeting and making friends with enthralling people at her new school and the inn.

Once a hot springs inn, now a boarding house with extraordinarily cheap rent, Yuragi-sou is virtually uninhabited save for a few peculiar residents. As rumor has it, it is haunted by a vile ghost which scares away all potential tenants. Therefore, it is the perfect refuge for Fuyuzora Kogarashi—a broke, homeless psychic seeking an affordable roof to stay under and ghosts to exorcise. Kogarashi prepares for a face-off against the ghost, only to find out it is not as malicious as the rumors made it out to be. Instead, it is the ghost of a beautiful, silver-haired girl whose only recollection of her life before death is her name: Yuuna. Even more baffling is that the other tenants of Yuragi-sou not only are able to see Yuuna as well, but each has their own supernatural ability. Amidst the chaos caused by his quirky fellow residents, Kogarashi attempts to uncover the regret that keeps Yuuna anchored to the world of the living, lest she become an evil spirit sentenced to spend her afterlife in hell.

One day after school, Asahi Kuromine stumbles upon the truth that Youko Shiragami, the girl he has a crush on, is actually a vampire. According to her father's rules, Youko must now quit school in order to keep her family safe. However, Asahi does not want her to go and promises that he will keep her true nature secret. Unfortunately, this turns out to be easier said than done, as Asahi is a man who is easy to read and is unable to keep any secrets to himself. And this is only the beginning of his troubles—more supernatural beings enter his life, and he is forced to protect all of their identities or face the consequences. Jitsu wa Watashi wa follows Asahi as he deals with his new friends and the unique challenges they bring, struggles to keep his mouth shut, and desperately tries to win Youko's heart in the process.

Nozomu Itoshiki is a high school teacher so pessimistic that even the smallest of misfortunes can send him into a pit of raging despair; some of these catastrophes even lead to suicide attempts. Sayonara Zetsubou Sensei is a satirical slice-of-life comedy set in the modern day, covering various aspects of Japanese life and culture through Nozomu and his interactions with his students: Kiri Komori, a recluse who refuses to leave the school; Abiru Kobushi, an enigma who frequently arrives to class with severe and mysterious injuries; the hyper-optimistic Kafuuka Fuura, Nozomu's polar opposite; and several other unusual girls, all of whom are just as eccentric as their teacher.