At eighteen years of age, Ventimiglia started auditioning, booking jobs, and working his way up. From there, Ventimiglia studied at UCLA before landing a role on The Fresh Prince of Bel Air. Ventimiglia has also guest starred on such television series as CSI: Crime Scene Investigation, Sabrina, the Teenage Witch, Law and Order: Special Victims Unit and Boston Public. He had the part of the main character, Jed Perry, in the short-lived FOX TV series, Opposite Sex. Milo also played a key role in an Apple advert for the Apple iBook.
From 2001 to 2004, Ventimiglia played brooding teen Jess Mariano on Gilmore Girls. He signed on for a spin-off of Gilmore Girls, entitled Windward Circle, which was going to be focused on the relationship between Jess and his estranged father (played by Rob Estes), but the proposed series never made it to air because of high filming costs. The season 3 episode Here Comes the Son, was the pilot for the California-set spin-off, which would have starred Ventimiglia, Rob Estes and Sherilyn Fenn. Ventimiglia returned to Gilmore Girls for a few episodes in seasons four and six since his 2003 departure.
In the third and final season of the NBC drama American Dreams, Ventimiglia played Chris Pierce, the rebellious boyfriend of Meg Pryor (Brittany Snow). Pierce and his single mother, Shelly (Daphne Zuniga), a Playboy bunny, move into the house next to the Pryors. Chris Pierce evades the draft, fearing he would be forced to fight in the Vietnam War, where Meg Pryor's older brother, J.J. (Will Estes) was wounded. Chris and Meg escape Philadelphia in the series finale to Berkeley, California, much to the sadness of Meg's best friend, Roxanne Bojarski (Vanessa Lengies).