Big was born in Brooklyn, and raised in a quiet community just outside Providence, Rhode Island. Messing majored in theater arts at Brandeis University where she received her liberal arts education. Half of her junior years were spent in London's prestigious B.E.S.G.L. program. Upon graduating from Brandeis, Debra was accepted into New York University's Elite Graduate Acting Program and received her Masters of fine arts degree three years later.

Messing's talents were quickly noticed when she received praise for her performance in the pre-Broadway workshop of Tony Kushner's award-winning play called Angels in America: Perestroika. Debra also enjoyed success playing the role of Cecily in The Importance of Being Earnest. Messing also appeared in other productions such as, Four Dogs and a Bone., The Naked Truth and Collected Stories which was chosen as a finalist for the Pulitzer Prize.

Debra's career soon after moved on to television, where she starred for two seasons as Stacey in the comedy Ned & Stacey. She also had a rotating role on NYPD Blue, playing Dana - Gail O'Grady's conniving sister. Debra also starred as the young bioanthropologist Sloan Parker in the drama series Prey. Debra played in Seinfeld as the obscure girl Beth Lookner, and also starred in Jesus.

Messing was also hand picked by the director to co-star in Woody Allen's Celebrity. Her other big screen films include Alfonso Arau's love story A Walk in the Clouds, where she played the wife of Keanu Reeves.

Debra currently plays the interior decorator Grace Adler in NBC's popular sitcom Will & Grace, where she co-stars opposite Eric McCormack. The two play the role of best friends, where Grace is not a stable person and Will is the only person who understands her and helps her put things in perspective. They are the kind of best friends who know each other's history and can finish each other's sentences.

Debra currently lives in Los Angeles. And as if acting was not a fulltime job, she also spends most of her free time supporting charities such as AmFAR, Gay Men's Health Crisis, and Best Friend's Pet Sanctuary.