Best known for her work on television sitcoms, she twice won the Primetime Emmy Award for Outstanding Supporting Actress in a Comedy Series for her role as Sally Solomon in 3rd Rock from the Sun.

She starred as divorce attorney Holly Franklin on The Exes, and as recovering addict Tammy Diffendorf on Mom.

She has also appeared in the films Austin Powers: The Spy Who Shagged Me (1999), The Flintstones in Viva Rock Vegas (2000), Music and Lyrics (2007), and Bride Wars (2009).

She performed with the Naked Angels Theater Company in The Stand-In and Hot Keys, and with New York Stage and Film in Kim's Sister with David Strathairn and Jane Adams.

[9] A Carsey-Werner casting agent who saw her in The Lights recommended her for the role of Sally Solomon on the TV series 3rd Rock from the Sun.

[10] After numerous auditions in 1996, she won the part[10] and starred on the show from 1996 to 2001, winning two Emmy Awards for Outstanding Supporting Actress in a Comedy Series.

Her significant roles in commercially successful movies include Austin Powers: The Spy Who Shagged Me in 1999, The Flintstones in Viva Rock Vegas in 2000, Music and Lyrics in 2007, and Bride Wars in 2009.

Johnston appeared in the sixth and final season of HBO's comedy drama series Sex and the City.

[17] Her memoir, titled Guts: The Endless Follies and Tiny Triumphs of a Giant Disaster was published on March 12, 2012 by Gallery Books.

[3] In 2018, she began a recurring role as Tammy Diffendorf on the CBS sitcom Mom, and was upgraded to series regular for the show's seventh and eighth seasons (2019–2020).

"[21] In May 2024, Variety announced that Johnston was cast in Netflix's upcoming comedy series alongside Leanne Morgan.