Takashi Natsume is a 15-year-old boy who wants nothing more but to live a normal life like everyone else. But to his dismay, like his deceased grandmother, Reiko, he possesses the ability to see "youkai," or spirits. Natsume eventually discovers that Reiko had bequeathed to him a book of contracts in which she had bound youkai—the "Book of Friends." However, without Reiko ever calling upon the spirits' names, they have been left in a confined state. Now, these spirits continuously pursue Natsume in the hopes of having their contracts dissolved for freedom.

While there may be gentle, harmless spirits which come to Natsume for help, there are also malicious, hostile spirits that threaten him. This is where Madara steps in, a spirit disguised as a rotund cat. Commonly referred to as Nyanko-sensei by Natsume, Madara is a self-proclaimed bodyguard who has his own motives for accompanying Natsume.

Natsume Yuujinchou is a supernatural slice-of-life series about a boy who struggles to live a normal life while balancing the spirit and human worlds and acquiring important life lessons along the way.