"Nyuru Nyuru!! Kakusen-kun" is a comedic anime series centered around Kakusen, a high school student who possesses the unique ability to transform into a sentient roll of toilet paper. This bizarre power stems from a curse placed on him by a mysterious entity, and it becomes the driving force of the series' humor and plot. Kakusen's transformation is triggered by stress or embarrassment, often leading to chaotic and absurd situations as he navigates his daily life.

The story primarily unfolds within the confines of Kakusen's high school, where he interacts with a colorful cast of characters. Among them is his childhood friend, Nadeshiko, who is aware of his condition and often tries to help him manage his transformations. Other classmates, such as the mischievous and unpredictable Kakeru, frequently exacerbate Kakusen's predicament, either intentionally or unintentionally, leading to further comedic mishaps. The series also introduces various antagonists, including rival students and supernatural beings, who challenge Kakusen and his friends in increasingly ridiculous ways.

Throughout the series, Kakusen struggles to maintain a semblance of normalcy while dealing with his curse. His transformations often result in public humiliation, but they also occasionally serve as a means to solve problems or protect his friends. The narrative balances slapstick comedy with moments of lighthearted camaraderie, as Kakusen and his peers grow closer through their shared experiences. The series does not delve deeply into dramatic or emotional arcs, instead focusing on episodic, gag-driven storytelling that emphasizes the absurdity of Kakusen's situation.

The humor in "Nyuru Nyuru!! Kakusen-kun" is heavily reliant on visual gags, wordplay, and the juxtaposition of mundane high school life with the surreal nature of Kakusen's abilities. The tone remains consistently light and comedic, with no significant overarching plot or dramatic stakes. The series is designed to entertain through its over-the-top scenarios and the endearing, if eccentric, personalities of its characters.