De Matteo's role in The Sopranos was one of her earliest, helping to launch her career. She has also appeared in several films including Swordfish, Deuces Wild, The Perfect You, Prey for Rock & Roll and the 2005 remake of John Carpenter's 1976 action film Assault on Precinct 13.
In 2004, de Matteo won an Emmy for Best Supporting Actress (Drama) for her role as Adriana on The Sopranos. She was also nominated for a Golden Globe that same year for the same role. She was ranked #42 and #56 on the Maxim Hot 100 Women of 2001 and 2002, respectively.
From 2004 to 2006, de Matteo portrayed Joey Tribbiani's sister Gina in the Friends spin-off Joey. The show was cancelled after two seasons.
Drea de Matteo is also playing the role of Wendy Case in an FX original series Sons of Anarchy. The pilot episode aired September 3, 2008.