"Jigoku Sensei Nube" centers around Nueno Meisuke, a fifth-grade teacher at Domori Elementary School, who harbors a dark secret: his left hand is a demonic entity sealed by his late mentor. Known as "Nube," he uses this cursed hand, called the "Devil's Hand," to exorcise malevolent spirits and protect his students from supernatural threats. Despite his fearsome power, Nube is a kind-hearted and dedicated teacher who deeply cares for his students, often going to great lengths to ensure their safety and well-being.

The series blends horror, comedy, and action, with each episode typically featuring a new supernatural incident. These incidents often involve vengeful spirits, cursed objects, or urban legends that threaten the school or its students. Nube, alongside his students, investigates and confronts these threats, using his Devil's Hand to combat the evil forces. His students, particularly Hiroshi Tateno and Miki Hosokawa, frequently assist him, forming a close-knit group that faces danger together.

Nube's past is gradually revealed throughout the series, including his training under his mentor, Ishiyama, and the tragic events that led to the sealing of the Devil's Hand. The narrative also explores the moral complexities of his power, as the Devil's Hand is both a weapon against evil and a potential source of destruction if misused. The series balances episodic supernatural encounters with overarching character development, particularly focusing on Nube's relationships with his students and his internal struggle to control his demonic power.

The tone of the series shifts between lighthearted humor and intense horror, often juxtaposing the innocence of childhood with the darker aspects of the supernatural. The students' perspectives provide a grounding element, as they navigate both the challenges of growing up and the terrifying realities of the spirit world. Nube's role as both a protector and a mentor is central to the narrative, emphasizing themes of responsibility, sacrifice, and the enduring bond between teacher and students.