De Matteo, an Italian American, was born in Queens, New York, the daughter of Donna, a playwright and playwriting teacher, and Albert De Matteo, a furniture manufacturer. She grew up in a Catholic family. After graduating from the Loyola School, she studied at New York University's Tisch School of the Arts, originally hoping to become a director, not an actress.
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 canceled 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.
In 2009, de Matteo was casted on ABC's Desperate Housewives as the new and mysterious housewife, Angie Bolen. She was the center of the season's mystery. She did not return for seasons seven and eight.
She lives in New York City, where she also formerly owned Filth Mart now located in Los Angeles, an East Village clothing store, with best friend and ex-boyfriend Michael Sportes. She is engaged to Shooter Jennings, son of Waylon Jennings. The couple had their first child together, a girl named Alabama Gypsy Rose, on November 28, 2007 and a son named Waylon Albert "Blackjack", on April 2011.
- Drea de Matteo at the Internet Movie Database