She gained national attention for her playing Jackie Harris on Roseanne (1988–1997, 2018), for which she won 3 Primetime Emmy Awards for Outstanding Supporting Actress in a Comedy Series, and its spinoff The Conners (2018–present).

Other film credits include Desperately Seeking Susan (1985), Uncle Buck (1989), JFK (1991), Dear God (1996), Georgia Rule (2007) and Scream 2 (1997).

[12] In 1981, she appeared as a feature player on the first Dick Ebersol-produced episode of Saturday Night Live following the firing of Jean Doumanian.

Her performance garnered four Primetime Emmy Award nominations for Outstanding Supporting Actress in a Comedy Series, a category that she won three consecutive times, from 1992 to 1994.

She also played minor roles in Warren Beatty's political drama Bulworth (1998) and the Garry Marshall romantic comedy Runaway Bride (1999).

Her biggest film role of the decade was as Susie Cox, one of Jim Garrison's chief investigators, in Oliver Stone's historical epic JFK (1991).

[17] Through this period, Metcalf had guest-starring roles on series such as Absolutely Fabulous, Malcolm in the Middle (as Susan Welker, Lois' younger sister), My Boys, Frasier, Portlandia, Without a Trace, and Grey's Anatomy, the last of which she played opposite her ex-husband Jeff Perry.

[20] Metcalf did not feature in many live action films during this period but she did appear in the raunchy comedy Beer League (2006), the Jim Carrey-led comedy remake Fun with Dick and Jane (2005), the coming-of-age drama Georgia Rule (2006) with Jane Fonda and Lindsay Lohan, and the war drama Stop Loss (2008) with Ryan Phillippe, Channing Tatum and Joseph Gordon-Levitt.

She would reprise the role repeatedly over its twelve-season run, and in 2016, her performance earned Metcalf her fourth nomination for the Primetime Emmy Award for Outstanding Guest Actress in a Comedy Series.

[18] Her daughter Zoe Perry portrays a younger version of Mary in the spinoff prequel series Young Sheldon.

[22] Metcalf ultimately relocated to New York City and began to work in theatrical productions such as David Mamet's November on Broadway in 2008, for which she received a Tony Award nomination.

[32] In 2012, Metcalf joined David Suchet in a West End production of Eugene O'Neill's Long Day's Journey into Night, for which she was nominated for the Evening Standard Theatre Award for Best Actress.

[38] In 2013, Metcalf starred in Bruce Norris's Off-Broadway play Domesticated with Jeff Goldblum at the Mitzi Newhouse Theater of Lincoln Center.

[40] She was nominated for the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series for its final season, losing to Julia Louis-Dreyfus of Veep.

's self-funded show Horace and Pete, for which she was nominated for the Primetime Emmy Award for Outstanding Guest Actress in a Drama Series.

's unflinching direction drinks her performance to the lees, to the point that Sarah's recollection of an afternoon sunbathing bristles with suspense, approaching the edge of some invisible precipice.

"[46] On April 28, 2017, it was announced that a revival of Roseanne was in the works and that Metcalf along with most of the original cast and some of the producers would return for the limited series that was being shopped around with ABC and Netflix the frontrunners to land the show.

[48] On May 29, 2018, in the wake of racist remarks by Barr posted on Twitter regarding former president Barack Obama's advisor Valerie Jarrett, ABC cancelled the revival after a single season.

[52] In 2018, Metcalf's portrayal of Jackie Harris earned a fifth Primetime Emmy Award for Outstanding Supporting Actress in a Comedy Series nomination for her work on the revival of Roseanne.

[53] Metcalf appeared on Broadway in Lucas Hnath's A Doll's House, Part 2 with Chris Cooper at the John Golden Theatre.

[54] In 2017, Metcalf received universal critical acclaim for her performance in Greta Gerwig's coming of age film Lady Bird starring alongside Saoirse Ronan and Tracy Letts.

[57] The following year Metcalf performed in the Broadway revival of Three Tall Women with Glenda Jackson and Allison Pill at the John Golden Theatre in 2018.

[62] It was reported in February 2020 that Metcalf would be starring in a Broadway revival of Arthur Miller's Death of a Salesman opposite Nathan Lane, though this has not come to fruition.

[63] In 2022 she portrayed Phyllis Gardner in the Hulu limited series The Dropout starring Amanda Seyfried as Elizabeth Holmes.

They also worked together on occasion, including in the 1994 feature film thriller Blink and the 1998 drama Chicago Cab;[68] they also appeared together in an episode of Desperate Housewives.