In the year 123 of the Universal Century, skirmishes between the Federation government and the rebel group Crossbones Vanguard echo across Earth's space colonies. One of these small battles breaks in the hometown of young Seabook Arno, forcing him and his friends to flee and ensnaring them in the political turmoil that is quickly evolving into an all-out war. Seabook meets Cecily Fairchild, granddaughter of the aristocrat Meitzer Ronah, who seeks to create a new political power called "Cosmo Babylonia." Using the Crossbone Vanguard as its muscle, the Ronah family schemes to restore aristocratic rule and establish an economic system that will benefit the nobility, thus devastating the quality of life for the common people of the Earth Sphere. Seabook is tasked with piloting the Gundam F91, a mobile suit created by his mother, and must choose between protecting the status Federation's status quo or cooperating with Cecily to find a better way of life for all.

The story revolves around five boys who each possess a trait that have negative effects on them. The handsome boys owe a monetary debt to Sakiko Horinomiya, a girl from a rich family. Wanting the money back, she makes them enter the "Motemen Koshien" contest, so they can pay her back using the prize money.

Mio has feelings for her childhood friend Arata, but can't convey her feelings. One day, as they continue their delicate relationship, the two fight over something trivial. After letting tensions settle, Mio goes to make up with him in the pouring rain. While on her way, she gets into a traffic accident. When she regains consciousness, a mysterious and unfamiliar world appears before her eyes.

While most fifteen-year-old boys, in one way or another, harbor secrets that are related to girls, Takashi Natsume has a peculiar and terrifying secret involving youkai: for as long as he can remember, he has been constantly chased by these spirits. Natsume soon discovers that his deceased grandmother Reiko had passed on to him the Yuujinchou, or "Book of Friends," which contains the names of the spirits whom she brought under her control. Now in Natsume's possession, the book gives Reiko's grandson this power as well, which is why these enraged beings now haunt him in hopes of somehow attaining their freedom. Without parents and a loving home, and constantly being hunted by hostile, merciless youkai, Natsume is looking for solace—a place where he belongs. However, his only companion is a self-proclaimed bodyguard named Madara. Fondly referred to as Nyanko-sensei, Madara is a mysterious, pint-sized feline spirit who has his own reasons for sticking with the boy. Based on the critically acclaimed manga by Yuki Midorikawa, Natsume Yuujinchou is an unconventional and supernatural slice-of-life series that follows Natsume as he, with his infamous protector Madara, endeavors to free the spirits bound by his grandmother's contract.