On his way home from his part-time job, Yuuya Amane finds two small cute creatures in a box looking for an owner. These said creatures are called "Nukos"—cats that have evolved with qualities closer to those of humans. As a result, they can speak words and feel human emotions while not straying too far from their catlike instincts. Curious about their nature and at the same time drawn to them, Yuuya assumes ownership of the two Nukos and offers his house as a place for them to stay.

Adorable and heartwarming, Nukozuke! depicts the everyday life of Yuuya and his two Nukos: Kei, a calico Nuko who acts mature despite often being mistaken for a girl, and Sasame, a black Nuko who is the younger of the two.