While heading home from his part-time job, Yuuya Amane discovers two small, cute creatures in a box seeking an owner. These creatures are known as "Nukos"—cats that have evolved to possess traits closer to those of humans. Consequently, they can speak and experience human emotions, all while remaining true to their feline instincts. Intrigued by their nature and simultaneously drawn to them, Yuuya takes ownership of the two Nukos and provides his home as a place for them to live. Adorable and heartwarming, Nukozuke! portrays the daily life of Yuuya and his two Nukos: Kei, a calico Nuko who behaves maturely despite frequently being mistaken for a girl, and Sasame, a black Nuko who is the younger of the pair.