Mazar was born in Queens, New York, the daughter of Nancy and Harry Mazar. Her father was born in the Latvian SSR, Soviet Union, to a Jewish family, while her mother was a Catholic who converted to Judaism and later became a Buddhist and for a period of time was a Jehovah's Witness.

Mazar began her career as a hip hop b-girl in New York City. Her first television appearance was on the pilot for a hip hop television dance show, Graffiti Rock in 1984. She appeared in four of Madonna's music videos - "Papa Don't Preach", "True Blue" (both 1986), "Deeper And Deeper" (1992) and "Music" (2000). Mazar has played a number of minor-yet-colorful supporting roles in a variety of movies, including: as Sandy, Henry Hill's girl on the side in GoodFellas (1990), The Doors (1991), Bullets Over Broadway (1994), and as Spice (of Sugar and Spice) in Batman Forever (1995). She gained her first real following from playing a character on Civil Wars in the early 90s. When that show was cancelled her character was brought over as a recurring role in the 1993 - 1994 season of the TV drama L.A. Law.

She played the villain Regina, a modern-day Cruella de Vil in the popular family film Beethoven's 2nd (1993). She has appeared in independent films like Inside Monkey Zetterland and Nowhere but has also dabbled in mainstream attempts like Batman Forever, and her short-lived sitcom, Temporarily Yours. (The sitcom was about a woman who, in an attempt to get a good apartment in New York City, lies about being employed with a temp agency and then shows up at the agency begging for work.) She also appeared as the genie in the Space Monkey's video, "Sugarcane".

Mazar appeared on a Friends episode in its eighth season ("The One Where Rachel Has a Baby, Part One"). Mazar played "Doreen, the Evil Bitch," a crazed pregnant woman who shares a hospital room with Rachel. She frequently refers to her husband as "sick bastard," "stupid bastard," and "sick son of a bitch" when she catches him creepily looking at Rachel. From 2000–2002 she played "Jackie" on the television drama That's Life.

Currently, she is in a supporting actress role on Entourage, an original comedy series on HBO. She also had a recurring role on the sitcom Living with Fran, playing Fran Drescher's character's cousin, Merrill. She also did a stint on the television series Ugly Betty, where she plays Leah Stillman, a scam artist who claims to be a lawyer in a number of episodes.

She married Gabriele Corcos on March 16, 2002, and they have two daughters: Evelina Maria, born on July 12, 2002, and Giulia Isabel, born on March 17, 2006. Mazar and Corcos are currently hosting a very successful internet show focused on Tuscan cuisine: Under The Tuscan Gun. The family divides their time between their home in Los Angeles and a fourteenth-century house outside of Florence that was given to them as a wedding present by Mazar’s in-laws.