Kannazuki no Miko begins in the village of Mahoroba, where time passes slowly for both man and nature. Two students from the village's prestigious Ototachibana Academy might as well be night and day. Himeko is shy and unassertive, while Chikane is bold and elegant. Despite this, they love each other, and nothing can come between them, no matter how hard they try. On the two girls' shared birthday, a sinister voice corrupts one of their friends into attacking them, and just when it seemed grimmest, the lunar and solar priestess powers that lay dormant in the two girls awaken, dispelling the evil. That was only the first hurdle, however. The two must now fend off the countless others who would threaten their well-being—even the people closest to them!

Sasahara Natsuki is a poor bounty hunter in a world where monsters and humans live together. Most of her cases involve monsters infringing upon the rights of humans, who are protected by law from their generally more powerful neighbors. Being half-human and half cat-beast, Natsuki straddles the two societies and tries to understand and respect both while enforcing the law. She is assisted by a werewolf named Batanen who is afraid to admit he loves her; another werewolf named Tommy; and a Kyubi fox demon named Sakura who has her own plans--which include eating Natsuki to complete her her nine tails and thereby her magical powers.

Finally, the day of Mai's high school graduation has arrived. While Sakuta eagerly waits for his girlfriend, an elementary schooler who looks exactly like her appears before him. Suspicious, and for all the wrong reasons... Meanwhile, Sakuta and Kaede's father suddenly calls, saying that their mother wants to see her daughter. She was hospitalized because Kaede's condition had been too much for her to bear, so what could she possibly want now?

Seto Ichitaka has a crush on Yoshizuki Iori, a girl in his class who has become so popular she now has her own fan club at school. But only a miracle could make him be with her, since the day he first saw Iori-chan, Ichitaka has been too shy to even talk to her. This miracle happened and now he and Iori are working together on the Freshmen Welcoming Party. It seems that things start to look bright for Seto, but then a special childhood friend is coming for a visit...