Buono was born and raised in the Bronx, New York, in a blue-collar family. She made her acting debut in Harvey Fierstein's play Spook House.
Buono is a 1995 graduate of Columbia University with a double major in English and Political Science. She earned her degree in three years.
Buono continued stage work both on Broadway and Off Broadway, and started her film career opposite Ethan Hawke and Jeremy Irons in Waterland (1992). Much of her work has been in indie films such as Chutney Popcorn (1999), Happy Accidents (2000), Next Stop Wonderland (1998) and Two Ninas (1999), which she co-produced.
Buono has directed, produced and written films, including the short film Baggage (1997), which starred Liev Schreiber. She co-wrote the screenplay When The Cat's Away with Brad Anderson, and sold a pitch to Miramax for a screenplay adaptation of F. Scott Fitzgerald's This Side of Paradise. She starred in the final season of the NBC drama Third Watch (1999) as Grace Foster. She appeared as Christopher Moltisanti's (Michael Imperioli) wife, Kelli, on the last two seasons of the HBO drama series The Sopranos, which aired in 2006 and 2007. She appeared as Dr. Faye Miller in the fourth season of the AMC drama series Mad Men.