Natsume Yuujinchou San follows Takashi Natsume, a boy who is able to see youkai. Natsume and his bodyguard Madara, nicknamed Nyanko-sensei, continue on their quest to release youkai from their contracts in the Book of Friends. Natsume comes to terms with his ability to see youkai and stops thinking of it as a curse. As he spends more time with his human and youkai friends, he realizes how much he values them both and decides he doesn't have to choose between the spirit and human worlds to be happy.

Due to an unusual ability to see strange creatures called youkai, Takashi Natsume has never fit in. Passed around from one foster home to another, he was left isolated and lonely. Over time, he has accepted that no one would ever believe him and has closed himself off to his current caretakers and classmates. 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, along with its power to call upon the written names of the youkai Reiko had defeated. 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, nicknamed Nyanko-sensei. With his newfound goal of freeing those Reiko had sealed, Natsume's relationship with both youkai and humans slowly begins to improve.

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. His most important ally is still his gluttonous and sake-loving bodyguard, the arrogant but fiercely protective wolf spirit Madara—or Nyanko-sensei, as Madara is called when in his usual disguise of an unassuming, pudgy cat. 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 Yuujinchou Shi is a sweeping but familiar return to a world of danger and friendship, where Natsume will finally confront the demons of his own past.

Traveling merchant Kraft Lawrence and wolf deity Holo sit down to have dinner with Norah Arendt, a young shepherdess who helped them smuggle gold. Holo's dislike of Norah—due to both the latter's profession and her closeness with Lawrence—prevents her from enjoying her meal. When Holo falls ill from fatigue, she is cared for by Lawrence, who frets over the health of his dear companion. As she regains her strength, Holo reminisces about the adventures they had together.