"Inui-san!" centers around the daily life and interactions of Inui Saku, a high school student with a unique and often misunderstood personality. Inui is known for her blunt honesty, lack of social awareness, and tendency to speak her mind without considering the consequences. Her straightforward nature frequently leads to awkward or humorous situations, especially in her interactions with classmates and teachers. Despite her quirks, Inui is not intentionally malicious; her actions stem from a genuine lack of understanding of social norms rather than any desire to cause trouble.

The narrative primarily unfolds within the school setting, focusing on Inui's relationships with her peers. Her closest friend, Yashiro Nao, serves as a foil to Inui's eccentric behavior. Yashiro is more socially adept and often finds herself mediating or explaining Inui's actions to others. Their dynamic highlights the contrast between Inui's unfiltered personality and the more conventional social expectations of those around her. Other characters, such as the class representative and various teachers, frequently find themselves caught off guard by Inui's unpredictable behavior, leading to a series of comedic and occasionally heartfelt moments.

The plot is episodic, with each episode presenting a new scenario or challenge that arises from Inui's unique perspective on life. These scenarios often involve misunderstandings, misinterpretations, or unintended consequences of her actions. For example, Inui might misinterpret a social cue, leading to a humorous exchange, or she might inadvertently reveal an uncomfortable truth, causing tension among her peers. Despite the comedic tone, the series occasionally delves into more reflective moments, exploring themes of individuality, acceptance, and the complexities of human relationships.

The humor in "Inui-san!" is largely derived from the contrast between Inui's unconventional behavior and the reactions of those around her. Her lack of awareness creates a consistent source of comedic tension, as characters struggle to navigate her unpredictable nature. At the same time, the series subtly underscores the importance of understanding and accepting differences, as Inui's friends and classmates gradually learn to appreciate her for who she is.

Overall, "Inui-san!" presents a lighthearted yet insightful exploration of social dynamics, individuality, and the challenges of navigating relationships in a world where not everyone fits neatly into societal expectations. The series balances humor with moments of genuine connection, offering a relatable and entertaining portrayal of high school life through the lens of its unconventional protagonist.