Nichijou focuses on the antics of a trio of high school girls—energetic Yuuko, cheerful Mio, and quiet Mai—whose lives intersect with a young genius Professor, her talking cat Sakamoto, and her anxiety-ridden robot caretaker Nano. What begins as a typical slice-of-life quickly devolves into the absurd, featuring everything from deer wrestling to random explosions.

Set in the fictional Tokisadame City, primarily revolving around Tokisadame High School and the Shinonome Laboratory. It appears to be a mundane suburban Japanese town, but it is populated by eccentric characters and operates on dream-like logic where the impossible is commonplace.