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.

Over three hundred years have passed since the Calamity War, the great conflict between Earth and its outer space colonies. Now Earth is ruled over by four economic blocs, and the military organization Gjallarhorn is responsible for keeping the peace. Mars, on the other hand, depends heavily on Earth's economy. Horrified by the appalling living conditions that Mars' inhabitants have to bear, Kudelia Aina Bernstein, a young aristocrat from the Chryse Autonomous Region, gets involved in the Red Planet's independence movement. She hires the services of a local company, Chryse Guard Security (CGS), to escort her on the journey to Earth to negotiate economic conditions with the earthly bloc that controls the region. The Third Army Division—consisting of Mikazuki Augus, Orga Itsuka, and many other child soldiers—are chosen to protect her. When Gjallarhorn attacks the CGS facilities to assassinate the young revolutionary threatening their interests, Orga and his comrades must not let the attackers accomplish their goal—in fact, Gjallarhorn's actions might turn out to be the unintentional catalyst that leads the children to be the forgers of their own destiny.

In a world inhabited by demons, cyclopes, and other fantastic creatures, humans stand apart as the outcasts. Quick to anger, the human race engaged in a war that all but wiped them out. The few humans that remain are seen as a delicacy, serving no purpose but to be hunted down and eaten. One day, a golem—a wandering protector of nature—encounters a lone human child while patrolling. Inspired by her enthusiasm, he takes the girl, named Somali, under his wing. Together, the duo embarks on a journey to find Somali's parents and bring her home.

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.