When Gintoki apprehends a movie pirate at a premiere, he checks the camera's footage and finds himself transported to a bleak, post-apocalyptic version of Edo, where a mysterious epidemic called the White Plague has ravished the world's population. It turns out that the movie pirate wasn't a pirate after all—it was an android time machine, and Gintoki has been hurtled five years into the future! Shinpachi and Kagura, his Yorozuya cohorts, have had a falling out and are now battle-hardened solo vigilantes and he himself has been missing for years, disappearing without a trace after scribbling a strange message in his journal. Setting out in the disguise given to him by the android time machine, Gintoki haphazardly reunites the Yorozuya team to investigate the White Plague, and soon discovers that the key to saving the future lies in the darkness of his own past. Determined to confront a powerful foe, he makes an important discovery—with a ragtag band of friends and allies at his side, he doesn't have to fight alone.

Kimito Kagurazaka is a commoner with a fetish for men's muscles—or at least that's the lie he must keep telling if he wants to keep himself out of trouble at the elite all-girls school, Seikain Academy. Kidnapped by the school under the assumption that he prefers men, Kimito is made to be their commoner sample, exposing the girls to both commoner and man so that the transition to the world after school is not jarring. Threatened with castration should his sexual preferences not match the school's assumptions, Kimito keeps up the facade to protect his manhood. But there are eccentric individuals around every corner who begin to make Kimito's life even more difficult. Among them are Aika Tenkuubashi, a social outcast who blurts out whatever comes to mind; Hakua Shiodome, a young genius; Karen Jinryou, the daughter of samurai who is obsessed with defeating Kimito; and Reiko Arisugawa, the perfect student who has delusions of marrying Kimito. Along with the commoner himself, these four girls make up the Commoner Club, which attempts to teach the girls more about life outside the school, while Kimito gradually learns about the odd girls surrounding him.

Tomboy Ryouko Ookami is a fierce boxer and the assigned bruiser of her club. Of course, no normal high school club needs a bruiser, but the Otogi Bank operates more akin to an actual bank. Here, the students can ask for favors from the club as long as they promise to return the favor in the future. Sixteen-year-old Ryoushi Morino is a shy boy, a far cry from the Otogi Bank members. To his biggest surprise, after unsuccessfully confessing to Ryouko, he inadvertently finds himself joining the club! Ookami-san to Shichinin no Nakama-tachi follows the everyday lives of the Otogi Bank members as they tackle favors that range from the mundane to the dangerous. However, since Ryoushi's sole motivation is to win Ryouko over, she doubts he will be able to have her back in a fight, especially when he can't even stand having people look at him—much less fight anyone!

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.