In Democrazia Cristiana, he was a member of Dossetti's lobby, together with Amintore Fanfani, Aldo Moro, and Giorgio La Pira. In 1951 he was elected national representative of young members; in 1958 he was elected deputy for the district of Rieti and Umbria.
He served as minister for Foreign Affairs (1979-80), Finance (1978-79), Instruction, Industry, State trades, and Mail and Telecommunications. He was also the President of the European Commission from 1970 to 1972; he resigned from this post to run for office in Italy. In the 1980s he was chief of the Italian delegation in the European Parliament. Politically close to Aldo Moro's lobby, Malfatti was among the participants in Bilderberg meetings.
His family donated his immense library to the University of Perugia.
Franco Malfatti (quasi homonymous of the one above) was an italian diplomat and became notorious when Aldo Moro, who had been kidnapped by the Red Brigades, wrote to ask him to solicit the assistance of Kurt Waldheim (at that time Secretary-General of the United Nations); however, ambassador Malfatti, then General Secretary of the ministry for foreign affairs, denied that this letter was ever received.