Lizzie McGuire (HILARY DUFF) is a typical teenager who's just graduated from middle school, but not without accidentally embarrassing herself in front of everyone. Accordingly, she's happy to be heading off to Rome for a two-week school trip with her best friend, David "Gordo" Gordon (ADAM LAMBERG).
They and a handful of classmates, including Ethan Craft (CLAYTON SNYDER) and Kate Sanders (ASHLIE BRILLAULT), will be under the supervision of high school principal Miss Ungermeyer (ALEX BORSTEIN) who's acting as their chaperone, but are hoping for some sort of great adventure.
They get that when Italian pop star Paolo (YANI GELLMAN) realizes that Lizzie is a near identical twin to his musical partner, Isabella (HILARY DUFF), whom he reports has flown the coup. Stating that they'll be sued if the duo doesn't show at a video awards ceremony, Paolo convinces Lizzie to act like Isabella and appear with him.
With bodyguard Sergei (BRENDAN KELLY) in tow, the two rehearse their act, which suddenly involves Lizzie having to sing on stage, much to her horror. At the same time, Lizzie's mischievous brother, Matt (JAKE THOMAS), convinces their parents, Sam (ROBERT CARRADINE) and Jo (HALLIE TODD), to fly to Rome. While they're on their way, Lizzie, Gordo and others try to keep her extracurricular activities secret from Ungermeyer as the big singing event nears.