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.

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.