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.

Despite a rough start, Makoto Misumi's life in another world takes a positive turn when he meets more demihumans who recognize his presence. Now as the leader of a fast-growing demihuman community, Makoto wishes to make human society more accepting of them and thus builds a business showcasing the demihumans' abilities. To extend his reach further, Makoto enrolls at the Rotsgard Academy to learn magic and expand his business venture there. Meanwhile, the goddess who summoned and forsaken Makoto had brought two other people to her world shortly after sending him away, making them heroes of their respective nations. Given enough time, Makoto's path will intertwine with both of these heroes, which may cause the world to take a drastic direction.

Amu Hinamori is a shy girl who struggles to make friends in part due to the rumors spread around school about her cool and spicy personality. Wishing that she could show everyone her would-be self, Amu wakes up to the presence of three colorful and ornately decorated eggs in her bed. Each of these Hearts Eggs houses a Guardian Character—manifestations of someone's would-be self and their dreams. With the aid of Ran, Miki, and Su, Amu now finds herself able to express who she truly is. However, things do not always pan out in her favor. The sudden appearance of Amu's Guardian Characters prompts the Seiyo Elementary Guardians, a student council-like group with each member possessing their own Guardian Character, to take notice of her. As someone who has multiple Characters, Amu is roped into being the Guardians' Joker, tasked with helping them find X Eggs—corrupted versions of one's Hearts Egg. As she becomes entangled in the Guardians' quest, Amu begins to uncover more about these mysterious Characters, the X Eggs, and the organization that seems to be at the center of it all.

Reito Mizuhara is a medical student at the National Advanced Medical School in Tokyo who contracts a rare, lethal disease called cellular sclerosis. In order to be treated, he is put into cryogenic sleep for five years. Upon awakening, he learns that a year into his slumber, a worldwide pandemic broke out, caused by the novel Male Killer (MK) virus which exclusively afflicts males and has killed all other men on Earth. Fortunately, Reito and four other men were spared during their cryosleep and are now immune to the virus. As the only men left in the world, they are thus tasked with mating with as many women as possible to repopulate the planet. However, Reito is committed to his childhood friend and sole love interest, Elisa Tachibana—only to learn that she went missing three years ago. While the other male survivors adapt accordingly to this new world, Reito instead chooses to pursue Elisa, fight never-ending temptation, and investigate this mysterious virus.