Messing landed her first television job in a recurring role on the hit dramaNYPD Blue in 1994. Her career advanced steadily from there, with guest spots on shows such as Seinfeld and a series of film roles: Keanu Reeves's wife in A Walk in the Clouds (1995), a bit part in Woody Allen's Celebrity(1998), and Mary Magdalene in the miniseries Jesus. Messing took her first star turn as comedic lead Stacey Colbert in the sitcom Ned and Stacey, opposite Thomas Haden Church. The show ran from 1995 to 1999.

In 1998, Messing landed the role that would make her a household name-that of Grace Adler, a neurotic interior decorator sharing an apartment with her gay best friend in the hit sitcom Will & Grace. Before accepting the role, Messing ensured she'd have the freedom to make her character "funny and unusual in a way that tickled me and surprised me," she recalled. "I didn't want to be the pretty straight woman. I knew I wouldn't be happy. I grew up watching Lucille Ball and Carol Burnett with curtain rods in her arms, falling down stairs. To me, that's funny." Will & Grace premiered on September 21, 1998. The show, one of the first major network programs to feature gay characters in starring roles, was considered rather controversial at the time. But audiences immediately took to the brash banter between Messing and co-stars Eric McCormack, Megan Mullally and Sean Hayes. "As much as this is an extraordinary premise because two of the four main characters were gay and we'd never seen this before, it was really a universal theme and that was friendship," Messing said of the show's success. The show remained a popular staple of NBC's prime-time lineup for eight seasons.

When Will & Grace wasn't filming, Messing continued to act in movies. She took roles in The Mothman Prophecies, Along Came Polly and The Wedding Date. She also played Woody Allen's girlfriend in the famed director's 2002 film Hollywood Ending, a role she viewed as a dream job. "I erupted!" Messing said, recalling the call from her agent telling her that Allen wanted her for the part. "This scream came from the lower depths of my body. I don't know how I didn't get into a car accident. It was as if I went blind for a minute with joy and shock."

Often compared to fellow redhead and physical comedienne Lucille Ball, Messing is a "natural comic talent ... beautiful, very, very gifted," in the esteemed judgment of Woody Allen. "She lights up everything she does."