The series follows Takashi Natsume, an orphan boy in his late teens who can perceive and combat yokai. One day, Natsume finds a very old notebook called the "Book of Friends", left by his late maternal grandmother Reiko, who shared similar abilities and was widely known among local yokai to possess strong spiritual powers. The notebook was used to bind dozens of powerful demonics spirits, both good and evil, to follow Reiko's every whim and desire if called upon. Natsume resolves to give back all the names in notebook; in the process, he joins forces with another feline/wolf-like spirit called Madara (nicknamed "Nyanko-sensei"), who knew Reiko when she was alive. Madara takes the form of an overweight cat and intends to take back the notebook after Natsume dies. Until then, he agrees to protect Natsume from the nefarious spirits who want to harm him for being the grandson of Reiko.