Other film appearances by Wiest include Footloose (1984), Woody Allen's The Purple Rose of Cairo (1985), Radio Days (1987), and September (1987), The Lost Boys (1987), Bright Lights, Big City (1988), Edward Scissorhands (1990), Little Man Tate (1991), The Birdcage (1996), Practical Magic (1998), Dan in Real Life (2007), Synecdoche, New York (2008), Rabbit Hole (2010), The Mule (2018), Let Them All Talk (2020), and I Care a Lot (2020).

[12] She also acted at the Yale Repertory Theatre in New Haven, Connecticut, playing the title role in Henrik Ibsen's Hedda Gabler.

[17] In 1976, Wiest attended the Eugene O'Neill National Playwrights Conference and starred in leading roles in Amlin Gray's Pirates and Christopher Durang's A History of the American Film.

However, she did appear onstage during the 1990s, in In the Summer House, Square One, Cynthia Ozick's The Shawl, and Naomi Wallace's One Flea Spare.

[28] In 2009, Wiest appeared in the National Memorial Day Concert on the Mall in Washington, D.C. in a dialogue with Katie Holmes celebrating the life of an American veteran seriously wounded in Iraq, José Pequeño.

[31] She reprised the role for Theatre for a New Audience in downtown Brooklyn, New York, in the spring of 2017,[32] and the Mark Taper Forum in Los Angeles in 2019.

Under Woody Allen's direction, Wiest won an Academy Award for Best Supporting Actress for Hannah and Her Sisters in 1987 and Bullets Over Broadway in 1995.

She also starred with Steve Martin, Mary Steenburgen, Jason Robards, Keanu Reeves and Martha Plimpton in Ron Howard's Parenthood, for which she received her second Oscar nomination.

Other major film roles include Tim Burton's Edward Scissorhands (1990), Jodie Foster's Little Man Tate (1991) and The Birdcage (1996), Mike Nichols' remake of La Cage aux Folles.

From 2000 to 2002, Wiest portrayed interim District Attorney Nora Lewin in the NBC crime drama Law & Order.

Wiest starred alongside Steve Carell and Juliette Binoche in Dan in Real Life (2007) and had a key supporting role in Charlie Kaufman's 2008 film Synecdoche, New York.

[17] Wiest has been nominated for three Academy Awards for Best Supporting Actress receiving two wins for her performances in the Woody Allen films Hannah and Her Sisters (1986) and Bullets Over Broadway (1994).