Takashi Natsume has grown accustomed to his encounters with youkai through the Book of Friends, which contains the names of youkai whom his grandmother, Reiko Natsume, has sealed in contracts. These encounters allow Natsume to better understand the youkai, Reiko, and himself.

The Book of Friends is a powerful tool that can be used to control youkai; it is sought after by both youkai and exorcists alike. Natsume just wants to live out his daily life in peace but is constantly disrupted by these experiences. If he is to end this torment, Natsume must explore more about the book and the world of exorcism, as well as begin to open his heart to those who can help him.

Takashi Natsume, the timid youkai expert and master of the Book of Friends, continues his journey towards self-understanding and acceptance with the help of friends both new and old.

Natsume, while briefly separated from Nyanko-sensei, is ambushed and kidnapped by a strange group of masked, monkey-like youkai, who have spirited him away to their forest as they desperately search for the Book of Friends. Realizing that his "servant" has been taken out from right under his nose, Nyanko-sensei enlists the help of Natsume's youkai friends and mounts a rescue operation. However, the forest of the monkey spirits holds many dangerous enemies, including the Matoba Clan, Natsume's old nemesis.

Stretching from the formidable hideout of the Matoba to Natsume's own childhood home, Natsume's Book of Friends Season 4 is a sweeping but familiar return to a world of danger and friendship, where Natsume will finally confront the demons of his own past.

Due to an unusual ability to see strange creatures called youkai, Takashi Natsume has never fit in. Over time, he has accepted that no one would ever believe him and has closed himself off.

When Natsume accidentally breaks an intangible barrier, he frees Madara—a mighty spirit in the form of a lucky cat. Madara notices that Natsume bears a remarkable resemblance to his late grandmother Reiko Natsume, an outcast girl who became known across the youkai world for creating the Book of Friends. It is now in Natsume's possession.

With no interest in its powers, Natsume decides to keep the book for the sake of his grandmother's memories and to protect it from scheming youkai. Therefore, he makes a deal with Madara: he will hand him the book once his time is up, and in turn, Madara will act as Natsume's unofficial bodyguard. With his newfound goal of freeing those Reiko had sealed, Natsume's relationship with both youkai and humans slowly begins to improve.