Natsume has always been an outcast because he inherited his grandmother's ability to see yokai. After moving to his grandmother's hometown and accidentally releasing a yokai imprisoned in a Lucky Cat statue, he learns about his grandmother's "Book of Friends," which contains the names of the yokai she defeated, and allows its wielder to command the yokai named within. Since then, yokai now visit him on a daily basis, seeking to either get their names back or take possession of the Book of Friends.

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.

Takashi Natsume has always been shunned by those around him because of his mysterious ability to see yokai. Eventually, he came into possession of his grandmother Reiko’s “Book of Friends,” and together with his bodyguard Nyanko-sensei he set out to return the names of the yokai contained within it. Since then, he’s found a home with the Fujiwaras and surrounded himself with friends at school. Little does he know he's about to be dragged unwittingly into further trouble...

Still in possession of his grandmother's Book of Friends, Natsume spends his days returning the names of yokai to their rightful owners. He has been learning how to deal with the yokai and humans that surround his life, but the time has come for him to deal with something even more difficult — his own past, and future.

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.