Following appearances in television movies and a commercial for Kool-Aid, at 13 she landed the role of Darlene Conner, the sarcastic middle child, in Roseanne.
Gilbert was a cast member in the show's nine-year run (1988–97), for which she wrote a fourth-season episode story (the teleplay was written by the Guild Writers for the show) called "Don't Make Me Over".
Her contribution was considered so important to Roseanne that the show's producers juggled storylines and taping schedules to allow her to study at Yale University while remaining in the cast, shooting remote segments of Darlene at a soundstage in New York.

Gilbert has appeared on The Simpsons, 24, Will & Grace, Law & Order: Special Victims Unit and Private Practice.
Starting in 2004, she had a recurring role as smart and sarcastic medical student Jane Figler on the long-running hospital drama ER; her appearances spanned seasons 11-13.

Gilbert regained a regular spot on prime time television in the fall of 2005 in the sitcom Twins on The WB network.
The show was canceled after one season, when the WB and UPN networks merged as The CW and dropped a number of series.
She also had a recurring role on the short-lived CBS sitcom The Class as Fern Velch.

From 2007 to 2010, Gilbert appeared in episodes of the CBS TV series The Big Bang Theory as Leslie Winkle, a scientist friend of Leonard Hofstadter played by Johnny Galecki, who had previously played Gilbert's love interest David Healy on Roseanne.
In the second episode of the second season of The Big Bang Theory, Gilbert was elevated to the show's main cast, portraying again a potential love interest of Galecki's character, and at one point a love interest to Howard Wolowitz (Simon Helberg).
By January 2009, it was announced that the writers did not know how to write for her character full-time, and her status was reduced from regular to recurring.
 Winkle was discontinued after Amy Farrah Fowler and Bernadette Rostenkowski became prominent characters.

Gilbert was a co-host and executive producer of The Talk, a talk show that premiered October 18, 2010.
Gilbert won a Daytime Emmy in 2016 for Outstanding Entertainment Talk Show as producer and creator of the show.
 Her final appearance as co-host was August 2, 2019.

An eight-episode revival series of Roseanne was developed, with Gilbert as an executive producer.
It was confirmed on May 16, 2017, and the eight episodes, picked up by ABC, began airing March 27, 2018.
Due to the revival's strong ratings and positive critical reception, a second season was announced.
However, on May 29, 2018, in the wake of controversial remarks made by Barr on Twitter regarding Valerie Jarrett (an advisor to former president Barack Obama), ABC cancelled the revival after a single season.
Gilbert distanced herself and the show from Barr's tweets saying that her comments are "abhorrent and do not reflect the beliefs of our cast and crew or anyone associated with our show".

On June 21, 2018, ABC announced that the network had ordered ten episodes of a spin-off of Roseanne.
That series, The Conners, featuring all of the regular cast except Barr, premiered in October 2018, with Gilbert starring and serving as an executive producer.
Following appearances in television movies and a commercial for Kool-Aid, at 13 she landed the role of Darlene Conner, the sarcastic middle child, in Roseanne. Gilbert was a cast member in the show's nine-year run (1988–97), for which she wrote a fourth-season episode story (the teleplay was written by the Guild Writers for the show) called "Don't Make Me Over". Her contribution was considered so important to Roseanne that the show's producers juggled storylines and taping schedules to allow her to study at Yale University while remaining in the cast, shooting remote segments of Darlene at a soundstage in New York.
Gilbert has appeared on The Simpsons, 24, Will & Grace, Law & Order: Special Victims Unit and Private Practice. Starting in 2004, she had a recurring role as smart and sarcastic medical student Jane Figler on the long-running hospital drama ER; her appearances spanned seasons 11-13.
Gilbert regained a regular spot on prime time television in the fall of 2005 in the sitcom Twins on The WB network. The show was canceled after one season, when the WB and UPN networks merged as The CW and dropped a number of series. She also had a recurring role on the short-lived CBS sitcom The Class as Fern Velch.
From 2007 to 2010, Gilbert appeared in episodes of the CBS TV series The Big Bang Theory as Leslie Winkle, a scientist friend of Leonard Hofstadter played by Johnny Galecki, who had previously played Gilbert's love interest David Healy on Roseanne. In the second episode of the second season of The Big Bang Theory, Gilbert was elevated to the show's main cast, portraying again a potential love interest of Galecki's character, and at one point a love interest to Howard Wolowitz (Simon Helberg). By January 2009, it was announced that the writers did not know how to write for her character full-time, and her status was reduced from regular to recurring.  Winkle was discontinued after Amy Farrah Fowler and Bernadette Rostenkowski became prominent characters.
Gilbert was a co-host and executive producer of The Talk, a talk show that premiered October 18, 2010. Gilbert won a Daytime Emmy in 2016 for Outstanding Entertainment Talk Show as producer and creator of the show.  Her final appearance as co-host was August 2, 2019.
An eight-episode revival series of Roseanne was developed, with Gilbert as an executive producer. It was confirmed on May 16, 2017, and the eight episodes, picked up by ABC, began airing March 27, 2018. Due to the revival's strong ratings and positive critical reception, a second season was announced. However, on May 29, 2018, in the wake of controversial remarks made by Barr on Twitter regarding Valerie Jarrett (an advisor to former president Barack Obama), ABC cancelled the revival after a single season. Gilbert distanced herself and the show from Barr's tweets saying that her comments are "abhorrent and do not reflect the beliefs of our cast and crew or anyone associated with our show".
On June 21, 2018, ABC announced that the network had ordered ten episodes of a spin-off of Roseanne. That series, The Conners, featuring all of the regular cast except Barr, premiered in October 2018, with Gilbert starring and serving as an executive producer.
Sara Gilbert