From a very politically active family to arise (Eleftherios Venizelos was his uncle, his father and both grandfathers were MPs), he took part against the German occupation of the island of Crete in the Cretan resistance struggle.
He studied at the University of Athens Law and Economics and was first in 1946 and then elected to Parliament as MP for the constituency of Chania to 1981, another ten times. From its family origins forth liberal, he belonged in the sixties, first the center Union of Georgios Papandreou, until it reaches the fall of the Papandreou government launched in 1965 as the leader of a group of " renegades " (Greek αποστάτες ), which he himself had been a member as Minister of Economics.
From the military junta, he was arrested after the coup d'état on 21 April 1967 but managed to escape and lived to 1974 in exile. After 1974, initially as an independent candidate is unsuccessful, he succeeded in 1977, the re-entry into parliament as a deputy of the small party 'New Liberal '. In 1978 he joined, founded by Konstantinos Karamanlis New Democracy. 1978 to 1980 he was Minister for Economic Coordination and 1980/81 Minister of Foreign Affairs.
In 1984 he was elected chairman of the New Democracy party. In addition to his arch-rival socialist Andreas Papandreou, son of Georgios Papandreou, he dominated in the eighties and nineties, the Greek politics. As party leader of the conservative New Democracy party, he could be certain in his Cretan homeland no longer a majority; he therefore ran from 1985 in Thessaloniki and Athens.
After his party had emerged as the winner in the parliamentary elections, he was elected in 1990 ( with a majority of one vote ) as prime minister. His government suppressed public spending, privatized state enterprises and initiated a reform of the public service. He attended the first Greek prime minister for 26 years, the U.S. and improved the poor under Papandreou relations with the United States.
In the parliamentary elections in 1993, the New Democracy party a parliamentary majority again lost to Papandreou's PASOK. Mitsotakis resigned as chairman of the New Democracy party, however, remained honorary chairman. In 2004 he retired from active politics.
His daughter, Dora Bakogianni, was from 2006 to 2009, Foreign Minister, his son Kyriakos Mitsotakis Member of Parliament.
In Greece Mitsotakis is considered notorious " bad luck "; in jokes and satirical anecdotes his presence with diverse misfortunes is associated.