"Mitsudomoe" centers around the chaotic lives of the Marui triplets—Mitsuba, Futaba, and Hitoha—and their homeroom teacher, Yūki Satō. The triplets, each with distinct personalities, bring constant mayhem to their sixth-grade classroom and the lives of those around them. Mitsuba, the eldest, is tomboyish and aggressive, often resorting to physical confrontations. Futaba, the middle sister, is shy and reserved but harbors a mischievous streak, frequently misunderstanding social cues. Hitoha, the youngest, is intelligent and mature beyond her years but has a dark, morbid sense of humor and a penchant for creating unsettling situations.

The series unfolds through a series of episodic comedic scenarios, primarily set in the classroom and the triplets' home. Yūki Satō, a well-meaning but often overwhelmed teacher, struggles to manage the triplets' antics while dealing with his own personal insecurities and romantic misadventures. His attempts to maintain order frequently backfire, leading to escalating chaos. The triplets' interactions with their classmates, including the timid Sugisaki and the eccentric Daigoro, further amplify the comedic tension.

Family dynamics play a significant role, with the triplets' father, Shinzō Marui, a single parent who often finds himself at the mercy of his daughters' unpredictable behavior. Despite their constant bickering and troublemaking, the triplets share a strong bond, and their antics often stem from a desire to protect or support one another, albeit in unconventional ways.

The humor in "Mitsudomoe" derives from exaggerated misunderstandings, slapstick comedy, and the stark contrast between the triplets' personalities. The series balances its over-the-top comedic moments with occasional heartfelt scenes, highlighting the underlying affection and loyalty within the Marui family and their relationships with others. The narrative thrives on its ability to escalate ordinary situations into absurd, laugh-out-loud scenarios, making it a lighthearted yet unpredictable viewing experience.