Doumori Elementary School, the familiar setting of supernatural chaos, remains under the protection of the only psychic teacher in Japan, Meisuke Nueno, known to everyone as Nube. In this sequel that follows directly after the events of Jigoku Sensei Nube Neo, Nube continues to teach a new generation of fifth graders in Class 5-3. These students include the earnest class leader Kento, the athletic and stoic Yuria, the mischievous Mari, along with Yuuki, Mamoru, and Seira. Though Nube is a clumsy, poor, and unpopular joker in daily life, he wields the fearsome Demon's Hand, a left hand that seals the power of a powerful demon, which he uses to battle the countless yokai, evil spirits, and urban legends that threaten his beloved students.

The series follows an episodic structure where the children encounter a supernatural entity born from a local rumor, a cursed object, or the lingering grudge of a disturbed spirit. These include the ghost of a girl named Elevator Eleko who died in a hospital and now crushes children in the elevator, a haunted rolling suitcase containing an oozy monster, cursed contact lenses, and a yokai called Sukina Onna that lurks in narrow gaps and walls. Nube typically arrives in the nick of time to exorcise the threat using his spiritual abilities, often revealing a tragic backstory for the monster and offering peace to the departed soul.

A recurring figure in these events is Nanafushigi Tarou, a mysterious high school student in a cap and uniform who appears to explain the nature of each haunting. Tarou, later revealed to be a monster himself with insect-like features, is not malevolent but genuinely fascinated by ghost stories and urban legends. As the series progresses, a much darker presence emerges in the forest outside Doumori: a cloaked psychic named Hachibanme no Roa, a man with a stone-cold face covered in tattoos who summons demons to terrorize children. Roa's motivation is revenge against children who mocked his wife's disfigured face after a horrific traffic accident. He summons a series of increasingly dangerous demons, including the terrifying Mozuchi, a winged beast with a face covered in eyes that grows stronger by devouring prey. Nube battles these threats while Tarou attempts to track Roa's movements. In the climactic final chapters, Roa launches an attack on the school itself, forcing Nube to face the villain directly and exorcise the summoned demons to restore peace to Doumori.