Mercouri was born in 1920 to a former cavalry officer and member of the Greek parliament, Stamatis Mercouris, and his wife, Eirini Lappa. When she completed her secondary education, she attended the National Theatre's Drama School, graduating in 1944. Mercouri's first husband was a wealthy landowner, Panos Harokopos; the couple divorced in 1962.
As an actress, Mercouri made her film debut in Stella (1955) and met international success with her performances in Never on Sunday (1960, with future husband Jules Dassin), Phaedra, Topkapi, and Promise at Dawn. She won the award for Best Actress at the 1960 Cannes Film Festival. She was nominated for an Academy Award, a Tony Award, three Golden Globe Awards, and two BAFTA Awards.
A political activist during the Greek military junta of 1967–1974, Mercouri became a member of the Hellenic Parliament in 1977 and became the first female Minister for Culture of Greece in 1981. In 1983, Mercouri proposed the programme of the European Capital of Culture, which was established by the European Union in 1985.
Mercouri was a strong advocate for the return to Athens of the Parthenon Marbles, which were removed from the Parthenon, and are now displayed in the British Museum in London.
After her graduation, Mercouri joined the National Theatre of Greece and played the role of Electra in Eugene O'Neill's play Mourning Becomes Electra in 1945. In 1949, she had her first major success in the theatre playing Blanche DuBois in A Streetcar Named Desire, written by Tennessee Williams and staged by Karolos Koun's Art Theatre. Until 1950, she also worked in the same theatre in other plays by Aldous Huxley, Arthur Miller and André Roussin.
Mercouri then moved to Paris, where she appeared in boulevard plays by Jacques Deval and Marcel Achard, and met famous French playwrights and novelists such as Jean Cocteau, Jean-Paul Sartre, Colette and Françoise Sagan. In 1953, Mercouri received the Marika Kotopouli Prize.
Mercouri returned to Greece in 1955. At the Kotopouli-Rex Theatre, Mercouri starred in Macbeth by William Shakespeare and L'Alouette by Jean Anouilh.
Mercouri's first movie was the Greek language film Stella (1955), directed by Zorba the Greek director Michael Cacoyannis. The film received special praise at the 1956 Cannes Film Festival, where she met American film director Jules Dassin, with whom she would share not only her career but also her life. Their first professional pairing was 1957's He Who Must Die. Other films by Dassin and featuring Mercouri followed, such as The Law (1959).
Mercouri became well-known to international audiences when she starred in Never on Sunday (1960), in which Dassin was the director and co-star. For this film, she earned the Best Actress Award at the 1960 Cannes Film Festival and was nominated for the Academy Award for Best Actress and the BAFTA Award for Best Actress in a Leading Role.
After her first major international success, Mercouri went on to star in Phaedra (1962), for which she was nominated again for the BAFTA Award and the Golden Globe Award for Best Actress in Motion Picture Drama. The recognition of her acting talent did not stop though, as her role in Topkapi (1964) granted her one more nomination, this time for the Golden Globe Award for Best Actress in Motion Picture Musical or Comedy. Mercouri worked with such directors as Joseph Losey, Vittorio De Sica, Ronald Neame, Carl Foreman, Norman Jewison, and starred in films like Spanish language The Uninhibited by Juan Antonio Bardem.
Mercouri continued her stage career in the Greek production of Tennessee Williams's Sweet Bird of Youth (1960), under the direction of Karolos Koun. In 1967, she played the leading role in Illya Darling (from 11 April 1967 to 13 January 1968) on Broadway, for which she was nominated for the Tony Award for Best Performance by a Leading Actress in a Musical. Mercouri's performance in Promise at Dawn (1970) earned her another Golden Globe Award nomination.
On 8 October 1962, Mercouri appeared on the American TV show What's My Line. After the panel were blindfolded, a strange man appeared on-stage and proclaimed himself "the second mystery guest". Host John Charles Daly quickly called for "the relieving unit" and said "schedule two" (a coded phrase used on live broadcasts in case of an emergency: the cameras are turned to a neutral position and the sound is cut off). The man talked a bit about a dating service he apparently owned before being hustled off the stage by announcer Johnny Olson and executive producer Gil Fates. Daly apologized to the panel and the program continued.
Mercouri concentrated on her stage career for the following years, playing in the Greek productions of The Threepenny Opera and, for a second time, Sweet Bird of Youth, in addition to the ancient Greek tragedies Medea and Oresteia. She retired from film acting in 1978, when she played in her last film, A Dream of Passion, directed by her husband, Jules Dassin. Mercouri's last performance on stage was in the opera Pylades at the Athens Concert Hall in 1992, portraying Clytemnestra.
One of her first songs was by Manos Hadjidakis and Nikos Gatsos. It was titled Hartino to Fengaraki ("Papermoon") 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 Melina had made for French television during the 1960s. Her recordings of "Athenes, ma Ville", a collaboration with Vangelis, and "Melinaki", were popular in France. Her recording of "Feggari mou, Agapi mou" (Phaedra) was quite popular and was later covered by Marinella in 1965.
At the time of the coup d'état in Greece by a group of colonels of the Greek military on 21 April 1967, she was in the United States, playing in Illya Darling. She immediately joined the struggle against the Greek Military Junta and started an international campaign, travelling all over the world to inform the public and contribute to the isolation and fall of the colonels. As a result, the dictatorial regime revoked her Greek citizenship and confiscated her property.
When her citizenship was taken away, she said: "I was born a Greek and I will die a Greek. Mr. Pattakos (the then Minister of the Interior of the junta who made these decisions against her) was born a fascist and he will die a fascist".
While in London she worked with Amalia Fleming and Helen Vlachos of Kathimerini against the junta of the colonels.
After the fall of the Junta and during the metapolitefsi in 1974, Mercouri settled in Greece and was one of the founding members of the Panhellenic Socialist Movement (PASOK), a centre-left political party. She was a member of the party's Central Committee and a rapporteur for the Culture Section, while being involved in the women's movement as well.
In the Greek legislative elections of 1974, she was a PASOK candidate in the Piraeus B constituency, but the 7,500 votes were not enough to secure a seat for her in the Hellenic Parliament (she needed 33 more votes), something that came true in the elections of 1977, in which she obtained the highest number of votes in the whole of Greece.
When PASOK won the elections of 1981, Mercouri was appointed Minister for Culture of Greece, being the first female in that post. She would serve in that position for two terms until 1989, when PASOK lost the elections and New Democracy formed a cabinet. As Minister for Culture, Mercouri took advantage of her fame abroad and got in contact with great European leaders in order to promote Greece. She strongly advocated the return to Athens of the Parthenon Marbles, that were removed from Parthenon and other buildings on the Acropolis of Athens by Thomas Bruce, 7th Earl of Elgin, and are now part of the British Museum collection in London. In anticipation of the return of the marbles, she held an international competition for the construction of the New Acropolis Museum, designated to display them and finally established in 2008.
One of her greatest achievements was the establishment of the institution of the European Capital of Culture within the framework of cultural policy of the European Union, that she had conceived and proposed in 1983, with Athens inaugurating this institution being the first title-holder in 1985, while she was a devoted supporter of the Athens bid to host the Centennial Olympic Games. In 1983, during the first Greek presidency of the Council of the European Union, Mercouri invited the Ministers for Culture of the other nine member states of the European Union at Zappeion, in order to increase the people's cultural awareness, since there was not any reference to cultural questions in the Treaty of Rome, which led to the establishment of formal sessions between the Ministers of Culture of the European Union. During the second presidency of Greece in 1988, she supported the cooperation between Eastern Europe and the European Union, which was finally implemented one year later with the celebration of the Month of Culture in Eastern countries.
Mercouri commissioned a study for the integration of all the archaeological sites of Athens to create a traffic-free archaeological park to promote the Greek culture. She introduced free access to museums and archaeological sites for Greek citizens, organized a series of exhibitions of Greek cultural heritage and modern Greek art worldwide, supported the restoration of buildings of special architectural interest and the completion of the Athens Concert Hall, backed the project of the Museum of Byzantine culture in Thessaloniki and established annual literary pizes.
In the legislative elections of November 1989, PASOK lost and Mercouri was elected a member of the Hellenic Parliament and remained a member of the party's Executive Bureau. In 1990, she was a candidate for Mayor of Athens but she was defeated by Antonis Tritsis.
After PASOK's win in the election of 1993, she was back at the Ministry for Culture. Her major goals in this second term in office were: to create a cultural park in the Aegean Sea in order to protect and enhance the environment and civilization of the Aegean Islands, and to link culture with education at all education levels, introducing a system of post-training of teachers.
Mercouri died on 6 March 1994 at Memorial Sloan Kettering Cancer Center, New York City, from lung cancer. She was survived by her husband, Jules Dassin. She had no children. She received a state funeral with Prime Minister's honors at the First Cemetery of Athens four days later. The Melina Mercouri Foundation was founded by her widower. After her death, UNESCO established the ‘Melina Mercouri International Prize for the Safeguarding and Management of Cultural Landscapes (UNESCO-Greece)' which rewards outstanding examples of action to safeguard and enhance the world's major cultural landscapes.