"A Destructive God Sits Next to Me" centers on the daily life of high school student Kabuto Hanadori, whose ordinary existence is disrupted when his eccentric classmate Seri Koyuki declares himself a god. Seri, who claims to be the creator of the universe, insists that Kabuto is his "vessel" and begins involving him in bizarre rituals and supernatural schemes. Despite Kabuto's initial reluctance and exasperation, he gradually becomes entangled in Seri's delusions, often finding himself dragged into chaotic situations.

The narrative unfolds through a series of comedic and surreal interactions, primarily focusing on the dynamic between Kabuto and Seri. Kabuto, a pragmatic and level-headed individual, serves as the straight man to Seri's flamboyant and unpredictable behavior. Seri's grandiose claims and eccentric actions are often met with skepticism from Kabuto, yet the latter frequently finds himself unable to escape the former's antics. Their relationship is further complicated by the presence of other classmates, including the stoic and mysterious Tsukimiya, who harbors her own secrets, and the cheerful yet clueless Mirei, who often becomes an unwitting participant in Seri's schemes.

The series blends elements of comedy, fantasy, and slice-of-life, with much of the humor deriving from the contrast between Seri's over-the-top personality and Kabuto's grounded reactions. While Seri's claims of godhood are treated as absurd by most characters, occasional hints of supernatural occurrences leave room for ambiguity, adding a layer of intrigue to the otherwise lighthearted tone. The story progresses through episodic scenarios, with each chapter or episode presenting new challenges or rituals orchestrated by Seri, often leading to chaotic and humorous outcomes.

Themes of friendship, individuality, and the clash between reality and imagination are subtly woven into the narrative, though the series primarily prioritizes humor and character interactions. The characters' relationships evolve over time, with Kabuto gradually developing a reluctant tolerance for Seri's antics, while Seri, in turn, begins to show moments of genuine care for his "vessel." The balance between absurdity and heartfelt moments creates a unique tone that distinguishes the series within the comedy genre.