"Jigoku Sensei Nube" centers on Nube, a fifth-grade teacher at Domori Elementary School, who harbors a secret: his left hand is a demonic entity sealed by a glove. This hand, known as the "Devil's Hand," grants him supernatural abilities, which he uses to protect his students from malevolent spirits and supernatural threats. Nube's dual role as an educator and exorcist forms the core of the narrative, blending horror, comedy, and action.

The series is episodic, with each episode or story arc focusing on a specific supernatural incident. Nube's students often find themselves entangled in these paranormal events, whether through curiosity, misfortune, or the machinations of evil spirits. Nube intervenes to resolve these situations, using his Devil's Hand to combat ghosts, demons, and other entities. His methods are unorthodox, often involving humor and unconventional tactics, which contrast with the darker themes of the series.

Key characters include Ritsuko Takahashi, Nube's colleague and love interest, who is unaware of his supernatural abilities for much of the series. Hiroshi Tateno, one of Nube's students, frequently becomes involved in the supernatural incidents, often serving as a secondary protagonist. Miki Hosokawa, another student, possesses a strong spiritual sensitivity, making her a frequent target for spirits. The series also features recurring antagonists, such as the malevolent spirit Kyōko Inaba, who seeks revenge against Nube.

The narrative explores themes of responsibility, sacrifice, and the coexistence of the human and supernatural worlds. Nube's commitment to his students and his willingness to risk his life for their safety underscore his role as both a protector and mentor. The series balances its darker elements with comedic moments, often derived from Nube's eccentric personality and the absurdity of the situations he faces.

As the story progresses, Nube's past and the origins of his Devil's Hand are gradually revealed, adding depth to his character and the overarching plot. The series also delves into the personal lives of the students and faculty, creating a sense of community within Domori Elementary. This blend of episodic storytelling and character development ensures that the series remains engaging while maintaining its focus on supernatural conflicts and Nube's dual identity as a teacher and exorcist.