After many minor film roles, Vartan had noticeable supporting roles in major movies, including Never Been Kissed (1999), One Hour Photo (2002) and Monster-in-Law (2005). In 2007, he appeared in the Australian horror film Rogue and will next star in the film Jolene.

Vartan's most notable role to date has been as Michael Vaughn in the American television series Alias (2001–2006). After appearing as a regular cast member through the first four seasons of the series, Vartan returned as a guest star in a limited number of episodes. He appeared as Vaughn in Sydney Bristow's dream in one episode, and beginning with the episode broadcast on April 19, 2006, he appeared in all remaining episodes. Vartan has also had guest appearances on Friends (as Dr. Tim Burke, Tom Selleck's character's son), Ally McBeal (as Jonathan Basset), and also Kitchen Confidential (as a rival French chef) starring his former Alias co-star Bradley Cooper. As of September 2007, Vartan is starring in the new AB