He was President of the Italian Catholic University Federation (FUCI) from 1942 to 1944, and was one of the founders of the Christian Democrat (DC) Party jointly with Alcide De Gasperi and Guido Gonella.
In 1944 he was elected a member of the National Council at the DC Congress in Naples.
In 1946 he was elected to the Constituent Assembly, re-elected in 1948 as a member of the Chamber of Deputies and was confirmed in all subsequent general elections until his appointment as a Senator for Life in 1991 for having honoured Italy with his outstanding merits in the social, scientific, artistic and literary fields.
He was Under-Secretary at the Office of the Prime Minister from 1947 to 1954, Minister for the Interior in the 1st Fanfani Government, Minister for Finance in the 1st Segni Government and the Zoli Government, Minister for the Treasury in the 2nd Fanfani Government, Minister for Defence in the 2nd Segni Government, where he remained under the following Tambroni, 3rd and 4th Fanfani, 1st Leone and 1st and 2nd Moro Governments.
From 1966 to 1968 he was Minister for Industry and Trade in the 3rd Moro Government and the 2nd Leone Government. In 1974 he returned to the Defence Ministry under the 5th Rumor Government.
On 17 February 1972 he became Prime Minister for the first time, but failed to win the vote of confidence. After the dissolution of the Parliament and the early elections called on 17 May 1972, on 26 June that year he formed his 2nd Government which remained until 12 July 1973.
He was Defence Minster in the 5th Rumor Government, and Minister for the Budget and Economic Planning from 1974 to 1976 in the 4th and 5th Moro Governments.
On 29 July 1976 he formed his 3rd Government, on 11 March 1978 his 4th, on 20 March 1979 his 5th Government which failed to win the parliamentary vote of confidence.
Between 1983 and 1989 he was Minister for Foreign Affairs in the 1st and 2nd Craxi Governments, and made detente the backbone of Italian foreign policy together with support for the Atlantic Strategy. He played a vital role in easing tension in the Middle East, supported the Eastern European countries in their democratisation process and the work of Gorbachev in the USSR, and gave permission for NATO to freely install Euromissiles in Italy.
In November 1985 he had to address the problem of the hijacking of the Achille Lauro liner by a group of Palestinian commandoes and the question of the American bombing of Libyan targets in Tripoli and Bengasi, when Libya launched two missiles against the island of Lampedusa, Italy cautioned Libya against any further acts of this kind.
Under the Craxi Government, Italy hosted the European Council in Milan which launched the challenge to create a Single European Market by 1992. For this purpose it approved the convening of an Intergovernmental Conference which, in February 1986,produced the Single European Act, which was the first organic institutional overhaul of the European Community. It was in that same six-month Presidency that Italy completed the negotiations for the accession of Spain and Portugal to the Community.
Andreotti was Minister for Foreign Affairs under the 6th Fanfani Government and the Goria Government and in December 1987, jointly with his Austrian colleague Mock, he concluded the terms of the Agreement on Alto Adige (the Italian South Tyrol) between Italy and Austria. He was also Foreign Minister under the De Mita Government.
On 22 July 1989 he formed his 6th Government and 12 April 1991 his 7th.