Nash made her professional acting debut in the 1995 film Boys on the Side. On television, she later guest-starred in NYPD Blue, Judging Amy, Reba, Girlfriends, CSI: Crime Scene Investigation and ER. She also appeared in 1999 film Cookie’s Fortune, and had a recurring role of CBS drama series, City of Angels, in 2000.

From 2003 to 2009, Nash played the role of Deputy Raineesha Williams and T.T. on the Comedy Central comedy series Reno 911!. In addition, Nash hosted Clean House on the Style Network from 2003 to 2010, as well as providing the voice of Mrs. Boots on the ABC Family animated series Slacker Cats, and starred as Rhonda, opposite Jerry O’Connell, in the short-lived Fox sitcom Do Not Disturb in 2008. She also has guest starred on The Bernie Mac Show as Bernie’s sister Bonita from 2003 to 2005. Nash won a Daytime Emmy in 2010 as the producer/host of “Clean House: The Messiest Home in the Country” in the category of Outstanding Special Class Special. On August 4, 2010 Nash announced she was leaving Clean House on the Style Network but the show will continue without her.

Nash was married for 13 years to Don Nash, an ordained minister, before filing for divorce in June 2007. They have three children together.

Nash appeared on the tenth season of ABC’s Dancing with the Stars beginning in March 2010, where she was partnered with Louis van Amstel. On May 11, 2010, Nash and van Amstel were eliminated from the competition, taking fifth place. In 2011 she got her own reality show Leave It To Niecy on TLC about her life with her new husband and step-son but it was quickly cancelled. In that same year she was in a TLC wedding special. She also appeared in films Code Name: The Cleaner (2007), Reno 911!: Miami (2007), Not Easily Broken (2009), G-Force (2009), and Trust Me (2013).

Nash became engaged to Jay Tucker on September 4, 2010. Nash participated in a TLC reality show that followed the preparations for the wedding. Nash and Tucker were married on Saturday, May 28, 2011, at the Church Estate Vineyard in Malibu. On October 30, 2019, Nash announced her pending divorce from Tucker via an Instagram post. The divorce was finalized on March 10, 2020.

In 2012, Nash began starring opposite Cedric the Entertainer in the TV Land sitcom The Soul Man, a spinoff from Hot in Cleveland. In 2013, she also began starring opposite Laurie Metcalf in the HBO comedy series Getting On. She received a Primetime Emmy Award for Outstanding Supporting Actress in a Comedy Series nomination for her role on the show in 2015 and 2016, as well as a Critics’ Choice Television Award for Best Supporting Actress in a Comedy Series in 2016.

In 2014, Nash played Richie Jean Jackson, the wife of Dr. Sullivan Jackson, in the historical drama film Selma, directed by Ava DuVernay. Selma received acclaim from critics; on Rotten Tomatoes, the film holds a rating of 99%, based on 205 reviews, with an average rating of 8.7/10. Selma was listed on many critics’ top ten lists. Also that year, Nash joined the cast of Fox comedy series, The Mindy Project in a recurring role as Dr. Jean Fishman, a rival of the title character.

From 2015 to 2016, Nash co-starred on the Fox horror-comedy series Scream Queens, as security guard, and then FBI Agent, Denise Hemphill. She appeared in another Fox comedy, Brooklyn Nine-Nine as Andre Braugher’s sister. The following year, she was cast in the leading role in the Fox comedy pilot The Enforcers. The pilot was not ordered to series. She also was cast in a recurring role as Louise Bell in the Showtime period drama Masters of Sex.

In 2017, Nash was cast in a leading role in the TNT crime comedy-drama series, Claws, produced by Rashida Jones about a South Florida nail salon. Also in 2017, Nash appeared in Mary J. Blige’s music video for “Strength of a Woman”. For her dramatic turn in Claws, Nash has received critical praise. She received a Satellite Award for Best Actress – Television Series Musical or Comedy, as well as another nomination for the NAACP Image Award for Outstanding Actress in a Comedy Series. In August 2018, it was announced that Nash would star in and produce Naked With Niecy Nash, a late-night talk show for TNT.

In July 2018, Nash received a star on the Hollywood Walk of Fame in the television category. Later that year, Ava DuVernay cast her in the Netflix limited drama series When They See Us. For her performance she received critical praise and a Primetime Emmy Award for Outstanding Lead Actress in a Limited Series or Movie nomination.

In 2020, Nash starred in the another Netflix feature drama film, Uncorked, directed by Prentice Penny, and well as had a recurring role in the Netflix comedy-drama Never Have I Ever created by Mindy Kaling. Also that year, she played civil rights advocate Florynce Kennedy in the Hulu miniseries Mrs. America. Later in 2020, Nash signed on to host her own syndicated daytime talk show for CBS Television Distribution.

On August 31, 2020, Nash announced that she and singer Jessica Betts had married, while coming out as bisexual.