The 10-year-old Matsuno sextuplets of Osomatsu-kun are given a glimpse of the future and see they're going to get fat, greedy and beaten up by angry girls.

Prehistoric versions of the brothers invent ways for them to relive any pent-up urges, with varying degrees of success. Later, Choromatsu and Ichimatsu struggle to make conversation with each other. After, Totoko takes part in an eating contest but keeps getting distracted by the brothers and guest star Shouei.

Iyami mooches off the sextuplets after falling on hard times and Hatabou searches for a friend.

The prehistoric sextuplets fool with nature for the last time. Several thousand years later, in a parody of Romance of the Three Kingdoms, Emperor Osomatsu and a group of bizarre generals attempt to take over the country. Meanwhile, in the real world, Osomatsu joins Todomatsu at a mixer, struggling to keep his perverted instincts in check.

Dayon uses Dekapan's latest invention to merge various people together into new beings, with a fiendish end goal in mind. Jyushimatsu becomes determined to get a job at a sea park as an actual dolphin, receiving strict training from a familiar female trainer. Meanwhile, Totoko and Nyaa encounter each other at Chibita's oden stand.

Ichimatsu struggles to get any sleep with his brothers being noisy all night and refusing to turn off the light. Unable to take anymore, Ichimatsu starts monitoring the brothers' courtesy towards each other, leading Osomatsu to get criticized the most. Later, Iyami proves his skills at the arcades by playing games at their highest difficulty.

Karamatsu tries to take on various requests from everyone to look like a reliable brother, only to take on more than he can handle, so Choromatsu tries to teach him how to refuse. Totoko begins working at a company, proving to be a handful for her superior Todomatsu. Later, a pair of seiyuu attend a dubbing session of an episode of Mr. Osomatsu, witnessing how the sextuplets do their work.

Already angered over the sextuplets refusing to paying off their oden tab, Chibita vows revenge on them after they pluck out his one-and-only hair. That night, Chibita begins taking out the siblings on by one, shaving all of their hair and stuffing oden in their bodies.

Jyushimatsu befriends a young boy named Eitarou but gets called in by Eitarou's mother when he starts imitating him. Later, Dayon steals Dekapan's underwear, forcing him to give chase all over the city and universe while butt naked.

A series of end-of-year skits. Osomatsu and Choromatsu try to do one thing that could make them say they had a good year. Ichimatsu gets persuaded to take part in a lottery, Dekapan and Dayon pound mochi together, Hatabou gets pestered by some greedy Jizou statues, and Choromatsu sends some untruthful New Years' cards. During the second half, a news crew documents Todomatsu, who was let go from the Matsuno family the previous year and is forced to try out for a reserve team.

Sanematsu wakes up in Osomatsu's world as the seventh Matsuno brother. Later, Jyushimatsu, Iyami, and Hatabou go on an expedition to find a Super Mongolian Death Worm. After, Choromatsu changes up his image by dying his hair brown, making it hard for his brothers to tell him that it's doesn't actually make him look cool.

The brothers struggle to remove the lid off of a particularly stubborn jar. After, Karamatsu runs his own taxi service, proving to have no idea what he is doing when he picks up an office lady played by Totoko. Finally, Totty holds a quiz for his brothers, containing several questions without right answers.

A group of aliens pursue the legendary space pirate, Shazarr. Later, displeased with Chibita's oden, Matsuzou serves up his own brand of the dish. Finally, the sextuplets become enamored by their new neighbor, Kinko Inuyama, prompting jealousy from Totoko when they go on a date with Kinko instead of her.

Ichimatsu becomes paranoid when lucky things happen to him all day, so he and Jyushimatsu try to punish themselves to balance things out. A lovey-dovey couple go to a hot spring inn that's haunted by a zashiki-warashi named Osoma.

In the 1960s, Iyami comes across a blind flower girl named Okiku and, despite being poor himself, tries to help her raise money for eye surgery.

After Dekapan becomes president, his secretary Todomatsu tries to keep him from pressing the Big Red Button. Iyami attempts to pull off a sham ventriloquism scheme by having Chibita and Hatabou act as his puppets. On Valentine's Day, the brothers try in vain to get some Valentine's chocolate from someone.

Yet another collection of random skits, with Dayon's live reaction complimenting. Chibita tries selling some sextuplet meat buns, Choromatsu files his taxes, Osomatsu accuses his brothers of stealing his wallet, a fierce wave of pollen hits town, Totoko tries to escape a creepy maze, raccoon Jyushimatsu cleans his food, Todomatsu tries doing something crazy, kindergartners visit a bread factory, the Proper-Rangers prepare to set off, and Osomatsu takes part in an Olympic skeleton event.

The brothers get rowdy while getting drunk at a restaurant. Unemployed office lady Totomi ends up taking a job at a strange establishment that offers some peculiar services. After being visited by a salesman, Matsuyo contemplates sending off one of her sons to a NEET correctional facility, asking Choromatsu to help her decide which one to send away.

Osomatsu and the rest take off for a wonderful Hawaiian vacation, only for disaster to strike, crashing Hatabou's private jet somewhere in the Pacific. How will our strange company survive the terrible desert island wilderness?

The Matsunos get drunk at the izakaya again. Dayon meets his doppelgänger. Iyami attempts suicide. The Matsunos get drunk at the izakaya one last time, but things turn introspective.

Matsuzou becomes hospitalized, leading the brothers to seriously think about their lives and get proper jobs to support their family. A chance meeting with Totoko sets Osomatsu's mind straight...

The Matsunos and Iyami are killed in a freak plane crash, sending them to Hell. In mourning, the others ponder a way to bring the status quo back to its rightful place with the help of someone near and dear to them.

Osomatsu-san returns in an all-new family-friendly incarnation! Surely nothing will go wrong, right?

Choromatsu, Todomatsu, and Ichimatsu discuss their expectations for the show's third season. Hatabou struggles to deliver an online food order. The sextuplets harass a touchy couple. Totoko plays an awful but beautiful doctor. Jyushimatsu and Karamatsu hang out in a konbini and find a strange ad. Two robots powered by AI arrive at the Matsuno home.

Osomatsu, Karamatsu, and Jyushimatsu share their expectations for the new season. The Riceballs estimate the value of the sextuplets' friends, causing embarrassment. Magical powers are given to the wrong girl.