Nueno Mesuke, better known as Nube, is a school teacher who does more than just teach. You see, Nube's left hand is a huge, nasty-looking demon's claw. He uses it to get rid of malicious demons, ghosts, spirits and other supernatural beings that are giving his students a hard time. Nube's left hand was normal, until one fateful day when he exorcised an extremely powerful demon from a child. He was outmatched and lost his left hand. The only way to fight it was to let it enter his body. As a result, Nube has a demonic left hand where his own hand used to be. To educate and protect — that is what Jigoku Sensei Nube does.

Meisuke Nueno (Ryuhei Maruyama) is the homeroom teacher of a 2nd grade 3 class in high school. He is referred to as Nube. He sometimes carries himself as an idiot, but he does care about his students a lot. He also has a hidden side. Meisuke Nueno has a demon's hand. He solves monstrous case and fights desperately to save students from monsters.

Kumiko Ijima is a very timid girl who happens to recognize a murderer still in pursuit at a park. With the help of her friend Kyoko Inaba, she warns the police about the wanted man. After trying to escape the police by car, the murderer crashes and ends up in the hospital. Some time later, a mysterious entity starts to terrorize the neighborhood in search of a girl who has the name initials K.I. and uses a red ribbon on her hair.

Nube gets a new student called Jun Kagami, a shy boy who has just transferred to Doumori Elementary School. Due to his insecurities, Jun believes that his only friend is a mysterious clown entity that lives inside mirrors. It is up to Nube to find out the true nature of this clown.

When Nube and his class arrive at a small island to carry out beach activities, they heard a forbodding tale from an old man residing on the island. Legend has it that there is a creature known as the sea spider in the open seas around the island. When the creature is past 200 years old, it will turn into a monster and devour humans to satisfy its appetite. However, curiousity kills the cat and Yukime decides to pursue the authenticity of the legend. And then, a girl suddenly appears on the beach. Possessed with a strange charm, she immediately attracts Hiroshi's attention and overcomes him. Soon later, strange things start to happen to the others whereby Kyoko and Ritsuko-sensei got attacked under strange circumstances. The true identity behind the mysterious girl is questioned and the legend behind the sea creature seems to be true after all.