Matarazzo made her film debut at age 12 in Welcome to the Dollhouse (1995), earning an Independent Spirit Award for her portrayal of Dawn Wiener.

Outside film, Matarazzo portrayed Heather Wiseman on the CBS series Now and Again (1999–2000), and had recurring roles on Roseanne (1997), Exes & Ohs (2006–2009), and The L Word (2007).

[4] Matarazzo began acting at the age of six; after commandeering the microphone at an AIDS benefit for children, she was given the card of a talent manager, with whom she remained for ten years.

She has commented that she is most proud of her performance in 1999's Our Guys: Outrage in Glen Ridge, based on a true story, in which she played a mentally challenged girl who is raped by football players.

Matarazzo has made appearances on several hit TV shows including Roseanne, Law & Order, The L Word, Grey's Anatomy and Strangers With Candy.