He was born at Potenza on 11 April 1920 and graduated in Law.
He was a member of Catholic organisations in which he held important offices, including the post of the National Vice-President of Catholic Action for Italian Youth.
He was a Deputy at the Constituent Assembly in 1946 and was elected to Parliament in 1948, and subsequently re-elected at every general election.
He entered Government for the first time as the Under-Secretary for Agriculture in the 5th and 6th De Gasperi Governments and subsequently as Under-Secretary for Public Works in the 8th De Gasperi Government, the Pella Government, the 1st Fanfani Government and the Scelba Government.
He was Minister for Agriculture and Forests in the 1st Segni Government and the Zoli Government, and one of the leaders of the Agricultural Reform designed by Antonio Segni. In 1958 he was Minister for Foreign Trade under the 2nd Fanfani Government, Minister for Industry and Trade in the 2nd Segni Government and the Tambroni Government and in the 3rd and 4th Fanfani Governments, Minister for the Treasury in the 1st and 2nd Leone Governments (and as Acting Minister for the Budget and Economic Planning) in the 1st, 2nd and 3rd Moro Governments and the 1st, 2nd and 3rd Rumor Governments.
From 6 August to 1970 to 15 January 1972 he served as Prime Minister, and on 6 March 1971 he was the acting Minister for Justice.
He served as Treasury Minister in the 1st Andreotti Government and as Minister without Portfolio with particular political and coordination duties and with particular reference to his post of the Italian Delegation to the United Nations, in the 2nd Andreotti Government.
He was Minister for Finance in the 4th Rumor Government, and returned to the Treasury under the 5th Rumor Government and the 4th and 5th Moro Governments.
He was elected to the European Parliament in 1976, and was elected President in 1977 and re-elected in 1979 in the first direct elections by universal suffrage to the European Parliament. That same year, in Aachen he was awarded the Charlemagne Prize, the third Italian statesman after De Gasperi and Segni. This prize is awarded every year to the European politician who has made the greatest contribution to the process of Community integration.
During the Eighties he returned to the government as Minister for Foreign Affairs under Cossiga and remained in that post under Forlani, Spadolini and Fanfani.
During this period, together with his German colleague, he drafted the Colombo-Genscher Act which constituted the political foundations on which the Single European Act for the Single Market and the Maastricht Treaty itself were subsequently based.
He also wrote the Declaration of Vienna on European policy for the Middle East.
In 1987 he was the Minister for the Budget and Economic Planning in the Goria Government and Minister for Finance in the De Mita Government.
In 1992, under Prime Minister Amato, he returned to the Foreign Ministry replacing the outgoing Foreign Minister Scotti. In September that year the EEC Monetary Committee suspended the Italian lira following the financial crisis. In that period, as a member of the Group of the 7 most industrialised countries, Colombo negotiated with his Russian colleague Kozyrev over the programme of Western economic aid to the Russian Federation for the launching of economic and social change. It was during his tenure at the Farnesina that the Single European Market came into effect on 1 January 1993.
On 14 January 2003 he was appointed Senator for Life for honouring Italy with outstanding merits in the social field.
He is currently the President of the Italian Atlantic Committee.