Drea de Matteo studied at New York University's Tisch School of the Arts, originally hoping to become a director, not an actress. Her 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, and the 2005 remake of John Carpenter's 1976 action film Assault on Precinct 13.
She has moved from dramatic roles to portray Joey Tribbiani's sister Gina in the Friends spin-off Joey.
In 2004, de Matteo won an Emmy for Best Supporting Actress (Drama) for her role as ill-fated Adriana on The Sopranos. She was also nominated for a Golden Globe that same year for the same role.
She currently lives in New York City, where she also formerly owned Filth Mart, an East Village clothing store, with best friend and ex-boyfriend Michael Sportes. She is currently dating Shooter Jennings, son of country music legend Waylon Jennings (1937-2002). De Matteo also said that while she dates men, she has had sex with women. 
She speaks fluent Spanish, which she learned as a child from her nanny.