One day, Takashi finds a very old notebook called the "Book of Friends", left by his late maternal grandmother Reiko Natsume, an exorcist who possessed strong spiritual powers.

The notebook was used to bind dozens of powerful demonic spirits, both good and evil, to follow Reiko's every whim and desire if called upon.

Takashi 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.

The Book of Friends is considered a highly prized item in the supernatural world, and such demons and spirits—both good and malicious—hunt Takashi constantly because of it.

Takashi also finds a good friend in an exorcist named Shuuichi Natori, who is also one of the very few humans who is capable of perceiving and taking down spirits via certain banishing or sealing spells, but also finds a dangerous adversary in Seiji Matoba, who has plans for Takashi to join him and his nefarious clan of exorcists.

Takashi is determined to release all of the names before the conniving Matoba clan or other malicious spirits attempt to use it for their own gain as he tries to learn whatever he can about his maternal grandmother and the strong spiritual connection they share.

Midorikawa created Natsume's Book of Friends as an episodic serial for a manga magazine published every two months, so that each chapter was a story that could be read on its own.

Natsume's Book of Friends has been adapted into an anime television series, directed by Takahiro Omori, and broadcast on TV Tokyo.

[112] A second theatrical anime, titled Natsume's Book of Friends: The Waking Rock and the Strange Visitor, premiered on January 16, 2021.

The main staff and cast members from the previous film returned to reprise their roles with the addition of Hisako Kanemoto as a guest-star.

The BD/DVD consisted of two discs, the second containing a clip of the "Sound Theatre × Natsume Yuujinchou: Tsudoi Ongeki no Shou" musical event which was held on September 28, 2013.

[123] A visual novel adaptation of the series, Natsume Yūjin-chō: Hazuki no Shirushi (夏目友人帳 ~葉月の記~), was announced in December 2024 by Bushiroad Games.