She has also acted in films such as Mac and Me (1988), Dead Again (1991), Black Sheep (1996), True Crime (1999), The Big Wedding (2013), The Wolf of Wall Street (2013), and Licorice Pizza (2021).

On television, she got her start on the soap opera Ryan's Hope (1977–1980) and as a cast member of Saturday Night Live (1981–1982).

She has co-starred on the TBS sitcom Sullivan & Son (2012–2014), the comedy-drama Royal Pains, the animated series Steven Universe (2018–2019), and the CBS sitcom Bob Hearts Abishola (2019–2024) Ebersole was born outside of Chicago in Winnetka, Illinois, the daughter of Marian Esther (née Goodley) and Robert "Bob" Ebersole.

Among her impersonations were Mary Travers, Cheryl Tiegs, Barbara Mandrell, Diana, Princess of Wales, and Rona Barrett.

[9] Following SNL, she appeared in One Life to Live as daffy Maxie McDermott (receiving an Emmy nomination) and Valerie.

She co-starred with Barnard Hughes on the sitcom The Cavanaughs, played the title role in the short-lived sitcom Rachel Gunn, R.N., and guest-starred on Will & Grace, Dolly!, Just Shoot Me, Murphy Brown, Ally McBeal, Samantha Who, Boston Legal, The Colbert Report, and Royal Pains.

[12][13] Ebersole's films have included Tootsie (1982), Amadeus (1984), Three Men and a Baby (1987), Mac and Me (1988), My Girl 2 (1994), Richie Rich (1994), Black Sheep (1996), and My Favorite Martian (1999).

[14] Off-Broadway, she has appeared in Three Sisters and Talking Heads, and her Broadway credits include On the Twentieth Century, the 1979 revival of Oklahoma!

[19] She appeared in the musical War Paint, which premiered at the Goodman Theatre in Chicago on June 28, 2016, for a run through August 2016.

[24] In November 2011, she performed for two sold-out nights at Birdland in New York City with jazz violinist Aaron Weinstein and his trio.

[7] She also released an album of Noël Coward songs after browsing through them for scene change music for Blithe Spirit.

[30] In 2012, Ebersole appeared on InfoWars' radio program The Alex Jones Show, expressing her misgivings about the Federal Reserve System and the Council on Foreign Relations.