She was born Anna Amalia Mercouri or Maria Amalia Mercouri, and became well-known to international audiences when she starred in the 1960 film Never on Sunday, directed by her husband Jules Dassin. In fact, she had been making movies since 1955, first appearing in the Greek film Stella.

The most important person in her early life, was her grandfather Spyros Merkouris, mayor of Athens for many decades. Her father was a member of the Parliament. The marriage of her parents ended when she was a youngster and she lived with her mother.

Her first lover was a Greek actor surnamed Papas, but she was first married, during her teenage years, to Panos Harokopos. She later maintained that although she loved her husband, their marriage was a mistake. He supported her need to become an actress, something that her family did not. They were married during the Second World War, and his wealth helped her to survive the difficult winters of the Nazi Occupation.

Nominated for an Academy Award for Never on Sunday, she went on to star in such films as Topkapi, Phaedra, and Gaily, Gaily.

Her first film Stella (1955) was directed by Michael Cacoyannis, the director of Zorba the Greek, and brought her to Cannes, where it was nominated for the Golden Palm. It did not win the prize, but she met there the man of her life, director Jules Dassin.

Jules Dassin is the father of Joe Dassin, the famous French singer who died in 1980 at the age of 41, and the actress Julie Dassin, by his previous marriage. Dassin and Mercouri did not have any children.

During the period of dictatorship in Greece from 1967 to 1974, Mercouri lived in France. When the dictatorship revoked her Greek citizenship, she said, "I was born Greek and I will die Greek. Mr. Pattakos was born a dictator and he will die as a dictator." During those years she recorded four records in France, one with Greek lyrics and the other three with French lyrics, all created by Greek musicians. They were highly popular, and they are still critically acclaimed and remastered. Her husky and unusual voice made her the perfect performer of some great Greek songs which are known classics and performed by hundreds of singers.

One of her first songs was by Manos Hadjidakis and Nikos Gatsos. It was titled Hartino to Fengaraki and was a part of the Greek production of A Streetcar Named Desire in 1949, in which she starred as Blanche DuBois. The first official recording of this, now-legendary song was made by Nana Mouskouri in 1960, although the company Sirius, created by Manos Hadjidakis, issued in 2004 a recording that Melina made for French TV during the 1960s.

When democracy returned to her home country, she returned, and became first a member of Parliament for PASOK, and then Minister of Culture. In 1971, she wrote her autobiography, I Was Born Greek.

Mercouri retired from film acting in 1978. Her last film, A Dream of Passion, was directed, as were most of her films, by her husband Jules Dassin. Her co-star in the film was Ellen Burstyn. In 1980, she starred in the Greek production of Sweet Bird of Youth by Tennessee Williams, in the lead role, which had been originated on Broadway by Geraldine Page.

As Minister of Culture, she proposed the Cultural Capital of Europe ideal within the framework of cultural policy of the European Community. Athens inaugurated this institution in 1986. She advocated the return of the Parthenon Marbles that Lord Elgin removed from the Acropolis. The Marbles are now a part of the British Museum collection. The return of the marbles is anticipated as a highly probable eventuality. For this reason a new museum is created under the Parthenon to host the collection and other pieces from the monument that are being removed and restored.

Mercouri died in 1994 in a New York hospital at the age of 73 from lung cancer. She was a heavy smoker and when she died, hundreds of Greek citizens left her favourite brand of cigarettes as a memorial at her shrine. Her body was returned to Athens and she received a state funeral equivalent to that of a Prime Minister.