Dukakis was born in Lowell, Massachusetts, the daughter of Alexandra and Constantine S. Dukakis. Her parents were Greek immigrants to the United States, her father from Anatolia and her mother from the Peloponnese. She has a brother, Apollo, and is a cousin of Michael Dukakis, a former governor of Massachusetts and the Democratic nominee for president in 1988, for whom she was a delegate from New Jersey at the 1988 Democratic National Convention. She is an alumna of Arlington High School in Arlington, Massachusetts, and was educated at Boston University.
Dukakis has been married to actor Louis Zorich since 1962. They have three children.
Dukakis has held a lengthy career in a diverse range of films, including Steel Magnolias, Mr. Holland's Opus, Jane Austen's Mafia!, The Thing About My Folks, and Moonstruck, for which she won an Oscar for Best Supporting Actress.
Dukakis won a BAFTA Award,and a Golden Globe for Moonstruck and was nominated for the Canadian Academy Award for The Event.