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. 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 created 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.

As with its prequel, Zoku Natsume Yuujinchou is about Takashi Natsume, a boy who has had the ability to see youkai since he was young, and his bodyguard youkai Madara, nicknamed Nyanko-sensei. Natsume attempts to return names written in his "Book of Friends" (which he inherited from his grandmother Reiko) to youkai in his village. Throughout these adventures, he meets some youkai that are friendly, some that want to steal the Book, and some that want to kill him, as Natsume learns about himself and his relationship with these mysterious beings along the way.

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.

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 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.

Blessed with eyes that are able to perceive the otherwise invisible youkai, Takashi Natsume hides his ability from his newfound family and friends to protect everyone's peaceful daily life. Meanwhile, the exorcist clan Matoba still wishes for Natsume to join their ranks due to his overwhelming gift. However, Natsume firmly rejects the clan's invitation since not all exorcists are as reasonable as his friend Shuuichi Natori, and many improperly and indiscriminately seal away every youkai in their way. Unsatisfied with Natsume's answer, Seiji Matoba blackmails Natsume into attending a grand gathering of powerful exorcist families. Natsume soon finds himself in the company of dangerous people and youkai alike. But even then, he continues to defy the exorcists' hard-handed methods and believes that peace between both worlds is possible.

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.

As a young child, Takashi Natsume believed his ability to see youkai to be nothing but a curse. Now a high school student, Natsume has managed to heal from his old wounds and form unbreakable bonds with humans and youkai alike. Natsume's newfound friendships—including the one with his spirit bodyguard Madara, nicknamed "Nyanko-sensei"—are often interlaced with his duty to return the names of the spirits written inside the Book of Friends, his late grandmother Reiko's keepsake. While more remarkable youkai reach out to him, Natsume discovers that he still has much to learn about the world that surrounds him.