She played Nancy Bartlett Thomas on the ABC sitcom Roseanne from the fourth season (1991) to the end of the show in 1997.

[15][16] The album was recorded in 1988 at the Orpheum and released in 1989 and the film was mostly shot on location in 1989 in the Cocoanut Grove nightclub at the Ambassador Hotel.

[17] During the run of Without You, I'm Nothing, With You, I'm Not Much Better Bernhard appeared with her then good friend (and rumored lover) Madonna on a 1988 episode of Late Night with David Letterman.

They continued to be friends for several years, with Bernhard making an appearance in Madonna's film Truth or Dare.

In 1996, she guest-starred on an episode of Highlander: The Series called "Dramatic License", where she played a romance novelist writing about the life of the main character.

She appeared as herself on Will & Grace, in an episode where the title characters spuriously bid on Bernhard's Manhattan apartment in an attempt to become friendly with her.

When their ruse is exposed, Bernhard rants at them, with the sounds of a blender (she was having a smoothie made) blotting out supposed obscenities.

[31] That year she also hosted the first season of the reality competition show The Search for the Funniest Mother in America on Nick at Nite.

[32][33] Bernhard was a featured guest singer with children's artist Dan Zanes on the Family Dance album's "Thrift Shop".

[35] In 2013, it was announced that she would join the cast of ABC Family's Switched at Birth with Glee's Max Adler, where she would play an art professor on the season 3 opener in January 2014.

From 2018 until 2021, she played Nurse Judy on FX's Pose, a show based on queer and trans ball culture in Manhattan inspired by the documentary Paris Is Burning.

In the commercial, promoting PlushGlass lipgloss, she referred to someone who might not approve of her outspokenness as a "little freaked out, intimidated, frightened, right-wing Republican thin-lipped bitch."

[41] In September 2008, she warned vice-presidential candidate Sarah Palin that she would be gang-raped by her "big black brothers" if she visited Manhattan.