"Isuca" is a supernatural action manga series that blends elements of comedy, ecchi, and fantasy. The story centers around Shinichirō Asano, a high school student who moves to a new town and becomes entangled in a world of demons and exorcists. He encounters Sakuya Shimazu, a skilled but financially struggling exorcist who is tasked with protecting the town from malevolent spirits known as "Isuca." These entities are summoned by humans through forbidden rituals and often wreak havoc unless subdued or destroyed.

Shinichirō inadvertently becomes involved in Sakuya's work when he discovers he possesses a unique ability: the power to nullify supernatural energy by biting his targets. This ability proves invaluable in combating Isuca, and he reluctantly joins Sakuya in her missions. Despite her formidable combat skills, Sakuya is often comically inept in everyday life, particularly in managing her finances, which leads to frequent humorous situations. The dynamic between the two characters evolves as they work together, with Shinichirō gradually adapting to the dangerous and chaotic world of exorcism.

The narrative introduces additional characters who play significant roles in the story. Tamako, Sakuya's younger sister, is a cheerful and supportive figure who assists in their battles. Other exorcists and supernatural beings are introduced as the story progresses, each with their own motivations and abilities. The plot delves into the origins of Isuca and the broader supernatural conflicts that threaten the town, revealing deeper layers of intrigue and danger.

The series balances action-packed battles with comedic and ecchi elements, often highlighting the absurdity of the situations the characters find themselves in. Themes of responsibility, loyalty, and the clash between the mundane and the supernatural are explored as Shinichirō and Sakuya face increasingly powerful adversaries. The manga maintains a steady pace, alternating between intense confrontations and lighter, character-driven moments, creating a blend of tension and humor that defines its tone.