Wiest's original ambition was to be a ballerina, but she began acting on Broadway, playing Desdemona to James Earl Jones' Othello. She made her film debut in 1980, but didn't make a name for herself until her performance as Emma, a prostitute during the Great Depression, in Woody Allen's The Purple Rose of Cairo (1985).

Under Allen's direction, Wiest won an Oscar for Best Supporting Actress, in Hannah and Her Sisters (1986). She followed her Academy Award success with performances in The Lost Boys (1987) and Bright Lights, Big City (1988) before starring 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.

In 1990, Wiest starred in Edward Scissorhands. She returned to Woody Allen in 1994 for Bullets Over Broadway, a comedy set in 1920s New York City, winning her second Best Supporting Actress Oscar for her portrayal of Helen Sinclair, a boozy, glamorous, and neurotic star of the stage.

She has recently appeared in the film Practical Magic (1998) and the television mini-series The 10th Kingdom (2000).

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

Wiest lives in New York City with her two adopted daughters, Emily and Lily. Recently, her daughter Emily and two teenage classmates from The Beekman School, a high school located in an East Side townhouse, were accused of robbing and beating up a fourth student on a midtown sidewalk after getting into a shoving and pushing match on school property.