"Usaru-san" centers on the daily life of Usaru, a high school student who unexpectedly becomes the caretaker of a mysterious, anthropomorphic rabbit named Usamimi. The rabbit, who possesses human-like intelligence and the ability to speak, moves into Usaru's home under peculiar circumstances. The narrative explores their evolving relationship as they navigate the challenges of cohabitation, blending slice-of-life elements with lighthearted comedy.

Usaru, initially reluctant to take on the responsibility, gradually forms a bond with Usamimi, who often provides quirky and humorous commentary on human behavior. The series delves into their interactions with classmates, family, and neighbors, highlighting the cultural and social adjustments required when a talking rabbit becomes part of a human household. Usamimi’s presence often leads to absurd yet endearing situations, such as attempts to attend school or participate in human activities, which are met with varying degrees of success and hilarity.

The supporting cast includes Usaru’s close friends, who react with a mix of curiosity and skepticism to Usamimi’s existence, and a few recurring characters who add depth to the story. Themes of friendship, responsibility, and acceptance are woven into the narrative, as Usaru learns to balance his own life with the demands of caring for an unconventional companion. The series maintains a light, episodic structure, with each episode presenting a new scenario or challenge for the duo to overcome, often culminating in humorous or heartwarming resolutions. The dynamic between Usaru and Usamimi serves as the core of the story, driving both the comedic and emotional moments throughout the series.