Gilsig began her career as a voice actress.
She has done voices in the films such as Masquerade, and for television series such as Young Robin Hood.

She moved to New York City in 1995 where she appeared in several off-Broadway plays.
However, it was her association with David E. Kelley that led to her starring role in Boston Public.

After guest-starring in two episodes of Kelley's The Practice, Gilsig was cast in two episodes of another Kelley program, the short-lived Snoops.
Although the series was cancelled before Gilsig's episodes were broadcast, Kelley wrote the part of Lauren Davis in Boston Public specifically for her, a series that premiered in September 2000 on FOX; Gilsig would leave the series after the end of the second season in May 2002.

Following her departure from Boston Public, Gilsig joined the cast of Nip/Tuck in 2003 as Gina Russo, a role she continued until 2008.
In 2004, she appeared in five episodes of NYPD Blue, followed by four episodes of FOX's Prison Break in 2005.

In addition to her extensive credits in television and theatre, Gilsig has appeared in film, beginning with a small role in the 1998 film The Horse Whisperer.
 She then provided the speaking voice for Kayley in the animated film Quest for Camelot (1998), with Andrea Corr performing the character's songs.
 In 2004 she appeared in Chicks with Sticks, as well as See This Movie, and in one of the lead roles in the 2007 movie Flood.

In 2007–2008 she had recurring roles in two television series, playing Shelley, the sister of Tami Taylor, on NBC's Friday Night Lights, and Claire Bennet's biological mother, Meredith Gordon, on Heroes.
Gilsig went on to play the main role of Terri Schuester on the Fox show, Glee, from 2009 to 2012.

In 2013, Gilsig was a series regular, portraying Siggy Haraldson, wife of Earl Haraldson and paramour of Ragnar Lothbrok's brother, Rollo, on the History Channel series Vikings until 2015.
In 2017 she joined the cast of Scandal.

On January 24, 2020, Gilsig joined the cast of the Disney+ sports comedy-drama series Big Shot as Bertha Russell with John Stamos to replace Shiri Appleby.
Gilsig began her career as a voice actress. She has done voices in the films such as Masquerade, and for television series such as Young Robin Hood.
She moved to New York City in 1995 where she appeared in several off-Broadway plays. However, it was her association with David E. Kelley that led to her starring role in Boston Public.
After guest-starring in two episodes of Kelley's The Practice, Gilsig was cast in two episodes of another Kelley program, the short-lived Snoops. Although the series was cancelled before Gilsig's episodes were broadcast, Kelley wrote the part of Lauren Davis in Boston Public specifically for her, a series that premiered in September 2000 on FOX; Gilsig would leave the series after the end of the second season in May 2002.
Following her departure from Boston Public, Gilsig joined the cast of Nip/Tuck in 2003 as Gina Russo, a role she continued until 2008. In 2004, she appeared in five episodes of NYPD Blue, followed by four episodes of FOX's Prison Break in 2005.
In addition to her extensive credits in television and theatre, Gilsig has appeared in film, beginning with a small role in the 1998 film The Horse Whisperer.  She then provided the speaking voice for Kayley in the animated film Quest for Camelot (1998), with Andrea Corr performing the character's songs.  In 2004 she appeared in Chicks with Sticks, as well as See This Movie, and in one of the lead roles in the 2007 movie Flood.
In 2007–2008 she had recurring roles in two television series, playing Shelley, the sister of Tami Taylor, on NBC's Friday Night Lights, and Claire Bennet's biological mother, Meredith Gordon, on Heroes. Gilsig went on to play the main role of Terri Schuester on the Fox show, Glee, from 2009 to 2012.
In 2013, Gilsig was a series regular, portraying Siggy Haraldson, wife of Earl Haraldson and paramour of Ragnar Lothbrok's brother, Rollo, on the History Channel series Vikings until 2015. In 2017 she joined the cast of Scandal.
On January 24, 2020, Gilsig joined the cast of the Disney+ sports comedy-drama series Big Shot as Bertha Russell with John Stamos to replace Shiri Appleby.
Jessalyn Gilsig