After graduating from New York University's Tisch School of the Arts, Messing starred in the television series Ned and Stacey on Fox (1995–1997) and Prey on ABC (1998).

She achieved her breakthrough role as Grace Adler, an interior designer, on the NBC sitcom Will & Grace (1998–2006, 2017–2020), for which she received seven Golden Globe Award nominations and five Primetime Emmy Award nominations for Outstanding Lead Actress in a Comedy Series, winning once, in 2003.

Messing's film work includes A Walk in the Clouds (1995), Jesus (1999), The Mothman Prophecies (2002), Hollywood Ending (2002), Along Came Polly (2004), The Wedding Date (2005), Lucky You (2007), The Women (2008), Nothing Like the Holidays (2008), Searching (2018), and 13: The Musical (2022).

[9] While Messing's parents encouraged her dream of becoming an actress, they also urged her to complete a liberal arts education before deciding on acting as a career.

[10] In 1993, Messing won acclaim for her performance as Harper in the pre-Broadway workshop production of Tony Kushner's play Angels in America: Perestroika.

In 1995, Messing made her film debut in Alfonso Arau's A Walk in the Clouds playing the unfaithful wife of main character Paul Sutton (Keanu Reeves).

Messing turned down a starring role in another television sitcom to appear in Donald Margulies's two-character play Collected Stories, which opened at the off-Broadway Manhattan Theatre Club.

In 1998, Messing played a lead role as the bioanthropologist Sloan Parker on ABC's dramatic science-fiction television series Prey.

In 2008, Messing reprised her role as Molly Kagan in the television series The Starter Wife, consisting of 10 episodes.

In February 2011, producers announced that Messing would star in a new NBC musical pilot called Smash for the 2011–2012 primetime season.

[16] Messing appeared with Green Day singer Billie Joe Armstrong and Leighton Meester in Frank Whaley's drama film Like Sunday, Like Rain in 2014.

[17] She made her Broadway debut in John Patrick Shanley's play Outside Mullingar alongside Tony Award winner Brían F. O'Byrne, which began previews at the Samuel J. Friedman Theatre on January 3, 2014.

Messing met Daniel Zelman, an actor and screenwriter, on their first day as graduate students at New York University in 1990.