Debra Messing was born into a Jewish family in the New York City borough of Brooklyn on August 15, 1968. When she was three she moved with her parent and her older brother, Brett, to a quiet town outside Providence, Rhode Island. Her father, Brian Messing, is a sales executive for a jewelry manufacturer; her mother, Sandy Messing, has worked as a professional singer, banker, travel agent, and real-estate agent. As a youngster Messing took lessons in dance, singing, and acting. "I remember watching the television show Fame and wanting to dance on top of a taxi," Messing told Jennifer Kasle Furmaniak for Cosmopolitan (February 2001). She recalled to Roz Brooks for Complete Woman (September 1999), "I was always singing and dancing for my mother when I wasn't glued to the television watching I Love Lucy or the Carol Burnett Show." While Messing's parents encouraged her dream of becoming an actress, they also urged her to get a standard liberal-arts education before deciding on acting as a career. Heeding their advice, she attended Brandeis University, in Walsham, Massachusetts. During her junior year she studied theater at the prestigious British European Studio Group of London program, in England, an experience that fueled her desire to act. After graduating summa cum laude from Braneis, in 1990, with a bachelor's degree in theater arts, Messing gained admission to the elite Graduate Acting Program at New York University (NYU), which accepts only about 15 new students annually. Three years later she earned a master's degree in fine arts from NYU.

In 1998 Messing had a lead role as the bioanthropologist Sloan Parker on ABC's dramatic science-fiction television series Prey, about a vicious new species of humans, spawned by global warming, who are determined to kill off all other humans. Although the show developed something of a cult following, Prey was canceled after one season. Meanwhile, Messing's agent had approached the actress with the pilot script for the television show Will & Grace, in which a heterosexual woman lives with a gay man who is also her best friend. Feeling tired after her stint on Prey, Messing was inclined to take some time off, but the pilot for Will & Grace intrigued her. In a conversation with Ian Williams for P.O.V. (November 1999), Messing described the visit to her apartment by the producers of Will & Grace one night; armed with a bottle of vodka and some limes, they tried to persuade her to join the show, which would pose a professional risk for everyone involved, because Will was to be depicted as openly gay. "I had to be assured by the producers that the very first priority, always, would be to make people laugh," Messing said to Williams. "Not to be critical. Not to proselytize. To make people laugh. People come home from work and they're tired and they want distraction; they want to laugh. And now, much to my shock, there hasn't been a right-wing revolt or picketing or exposes about how we're ruining America. Because the show is funny first."

Directed by James Burrows, who also directed Cheers, Frasier, Seinfeld, and Friends, and created by Max Mutchnik and David Kohan, Will & Grace was an instant success. After eight years with the show, Messing was ready for a break from television. "Three months later. My agents sent me the script [to The Starter Wife] and said, 'Just read it.'...it was so smart and funny, I was compelled to do it." Messing said to Liz Welch of Redbook (June 2007). The miniseries based on the novel premiered on USA on May 31, 2007 landing Debra as Molly Kagen an Emmy nomination for outsanding lead actress in a miniseries or movie, a Golden Globe nomination for best actress in a miniseries or television film among others. USA approved the miniseries for 10 episodes as a TV series the following season with Messing again as Molly Kagan and Messing as a producer. Although Messing was nominated for a Golden Globe for best actress in a television series musical or comedy, The Starter Wife was cancelled by USA in February 2009.

Messing's big-screen roles include Edie Cohen in the The Women (2008); Sarah Rodriguez in Nothing Like the Holidays (2008); Suzanne Offer in Lucky You (2007); Kate Scott in Purple Violets (2007); the voice of Beth in the animated film Open Season (2006); a starring role as Kat Ellis in The Wedding Date (2005) opposite Durmot Mulroney; a happily married but ill-fated wife in the supernatural thriller The Mothman Prophecies (2002), which stars Richard Gere; Lieutenant Penelope Carpenter in the inconsequential remake of the military comedy McHale's Navy (1997); and Mary Magdalene in CBS's biblical television movie Jesus (1999). Her stage work includes a stint as an understudy to Mary Louise Parker and Polly Draper in the Off-Broadway production of Four Dogs and a Bone (1993) and a co-starring role in Paul Rudnick's play The Naked Truth (1994). In the early 1990s she also had a role in a Seattle production of Oscar Wilde's play The Importance of Being Earnest.

With her recognized talent for physical comedy and her luxurious head of curly auburn hair (which is sometimes described as red and has brought her jobs as a spokesperson for hair-care products), Messing has drawn comparisons to the legendary redheaded comedic television actress Lucille Ball. Cosmopolitan (February 2001) named Messing the magazine's Fun Fearless Female of the Year. "I love to do glamorous things, like wear Valentino," the photogenic Messing told Furmaniak, referring to the celebrated Italian fashion designer. "That's a part of me that will never go away, playing dress up in my mom's closet and looking at pictures of old Hollywood stars." Messing is a supporter of the charities AmFAR, an organization that combats AIDS; the Gay Men's Health Crisis; and Best Friend's Animal Sanctuary.

Messing met her future husband, Daniel Zelman, an actor and screenwriter, on their first day as graduate students at NYU. "He was different from anyone I'd been interested in before. I'm so right out on the table. But he was quiet and introspective. I couldn't stop wondering about him," Messing recalled in an article that appeared in Entertainment Tonight (February 12, 2002, on-line). She and Zelman, who were married on September 3, 2000, live in Los Angelas. Weighing in at 5lbs 14oz, Debra gave birth to her son, Roman Walker Zelman on April 7, 2004. "For the first two months, I did nothing but breast-feed and spend day and night gazing into my son's eyes.... Motherhood is wonderful. I'm madly in love," Messing said to Steve Gidlow of Red (December 2004). And despite the problems that arose with her first pregnancy, in another interview with Red (November 2006), Messing tells Francesca Babb "I think if I were to have more, it would only be one. We would have five more and love every one of them, but it's just a matter of wanting there to be a manageable amount of chaos." Messing told Carol Mithers of Town & Country (September 2008), "Today the family leads a quiet life. The biggest challenge is the ambivalence I feel whenever I spend time with my son and realize how much he grows and changes every day. Work isn't about me anymore or whether or not I'm 'creatively fulfilled.' I want to spend every extra minute I have with my son."