Yachiyo Inugami, an outgoing girl who loves cats, and Suzu Nekoyama, a reserved girl who loves dogs, are thrown into a relationship on an ordinary day. The two are pulled together by an inexplicable attraction born from their opposing personalities. As they start to understand each other quickly, Inugami's strong determination to win Nekoyama's affection only results in frantic reactions. Shortly after their significant union, they begin spending more time together, steadily growing closer.
Their combined antics catch the attention of the timid Mikine Nezu, a classmate of Inugami, and soon they all join the "biology" club. There, they meet Ushikawa Ukiji, a passive senior with a cow-like demeanor. Nezu and Nekoyama soon start building on their relationship, and a game of cat and mouse begins.
Wild, explosive, and vibrant, Inugami-san to Nekoyama-san tells the comedic story of two high school girls and their far-from-ordinary relationship.