She is known for playing Peggy Bundy on Married... with Children (1987–1997), Leela on Futurama (1999–2003, 2008–2013, 2023–present), Cate Hennessy on 8 Simple Rules (2002–2005), Gemma Teller Morrow on the FX series Sons of Anarchy (2008–2014), for which she won the Golden Globe Award for Best Actress – Television Series Drama in 2011, and Louise Goldufski-Conner on The Conners (2018–present).

[7] In 1977, Sagal's father married dancer/actress Marge Champion, a few years before his accidental death on the set of the miniseries World War III in 1981.

In 1973, she worked as a backing vocalist for various singers, including Bob Dylan, Etta James, and Tanya Tucker.

[16] She performed the song "It's the Time for Love" that appears in the film Silent Rage (1982) featuring Chuck Norris.

Sagal also provided the vocals for "Loose Cannons," the theme song for the 1990 film of the same name featuring Gene Hackman and Dan Aykroyd.

[29] One of Sagal's early roles was as a receptionist in the Columbo installment "Candidate for Crime" (1973), which was directed by her father Boris.

[32] Reportedly Sagal brought her own red bouffant wig to audition for the role, and with the producers' approval the look transitioned into the show.

[33] However, Sagal later explained that she had initially styled her own hair, then once the show took off, the producers began to invest in a wig.

In 1998, Matt Groening chose her to provide the character voice of the purple-haired mutant spaceship captain, Leela, in his science-fiction animated comedy Futurama.

[40] Sagal was cast as the wife of John Ritter in the sitcom 8 Simple Rules for Dating My Teenage Daughter in 2002.

[44] From 2008 to 2014, Sagal starred as Gemma Teller Morrow on the TV show Sons of Anarchy, whose creator, Kurt Sutter, she had married in 2004, four years before the series premiered.

[51] On September 9, 2014, Sagal received a star on the Hollywood Walk of Fame; the Married... with Children cast – Ed O'Neill, Christina Applegate, and David Faustino – were present to celebrate the actor's recognition.

[52] On September 20, 2016, Sagal appeared on The Big Bang Theory as Susan, the mother of Penny (Kaley Cuoco).

[56] On February 9, 2022, Hulu announced that streaming service would be reviving Futurama for a 20-episode 11th season run set to premiere in 2023 with Sagal returning as the voice of Leela.

[57] In 2023, Sagal appeared live off-broadway in The Gospel According to Heather, which was written by Paul Gordon, directed by Rachel Klein and produced by Amas Musical Theatre and Jim Kierstead.

The showrunners did not want to subject a grieving Sagal to further stress by interacting with an infant during filming, so the pregnancy on the show (as well as the pregnancy of co-star Amanda Bearse's character) was then treated as a "dream sequence," which was mentioned only briefly at the end of the episode "Al Bundy, Shoe Dick."

In scenes where Peg was shown, Sagal had her midsection obscured, such as when she was sitting in a taxi or at a craps table in Las Vegas and was often seen or heard talking to family members over the phone.

[63] The loss of her stillborn daughter Rudy[64] was the inspiration to write the lyrics for "(You) Can't Hurry the Harvest".