The series was known by the working title 'What's Lizzie Thinking?' throughout development before being retitled Lizzie McGuire.

Producer Stan Rogow conceived the idea of an animated version of Lizzie to visually convey her inner thoughts, a concept originally envisioned as just a talking head in the corner of the screen; Rogow stated the show's visual design was inspired by the film Run Lola Run.

Independent animator Debra Solomon designed the animated Lizzie based on Hilary Duff's audition tape, giving her a 'hip' look with cropped shirts, trim pants, and flip-flops; due to Disney's low budget, each episode only contains about two minutes of animation.

Hilary Duff auditioned for the role of Lizzie in 2000, described simply as a regular teenager.

The first episode actually filmed, 'Pool Party', ended up airing as the fourth episode, with production of the rest of season one beginning around six months later.

According to a 2024 book on Disney Channel's history, Lalaine and Hilary Duff had an irreparable falling-out during the final stretch of filming season two, which led to Lalaine's character Miranda being written out of the last six episodes and absent from The Lizzie McGuire Movie.

A canceled spin-off pilot centered on Miranda's younger sister Stevie Sanchez was produced in 2005, starring a young Selena Gomez in the lead role, but it was passed over in favor of Hannah Montana.

Production on the 2019 Disney+ revival series began on location in Washington Square Park in New York, but was placed on hiatus after showrunner Terri Minsky departed over creative differences with Disney, and the revival was officially canceled in December 2020.