Yachiyo Inugami, a cat-loving extrovert, and Suzu Nekoyama, a dog-loving introvert, are unexpectedly cast into a relationship on a day like any other. The pair find themselves drawn together through an inexplicable attraction of their opposite personalities. As they quickly begin to understand one another, Inugami's hardened resolve to gain Nekoyama's favor only leads to frenzied responses. Soon after their momentous union, the two begin to spend more time with one another, growing closer all the while.

Their combined antics gain the attention of the mousy Mikine Nezu, a classmate of Inugami, and soon they join the "biology" club. There, they meet Ushikawa Ukiji, a passive, cow-like upperclassmen. Nezu and Nekoyama soon begin to build upon their relationship and a game of cat and mouse soon begins.

Wild, explosive, and vibrant, Inugami-san to Nekoyama-san tells the comedic tale of two high school girls and their less-than-normal relationship.