Zaccagnini was among the founders of the Christian Democracy (DC), and was elected at the Constituent Assembly (1946) and the Chamber of Deputies (1948) of the new-born Italian Republic. He was a member of the Christian Democratic wing more favourable to a collaboration with left (or centre-left) parties. He was confirmed at the Chambers of Deputies until 1979, when he was elected to the Italian Senate.
In 1959, Zaccagnini was appointed Minister of Labour and Social Security in the Segni II Cabinet, a position he maintained also in the following government led by Fernando Tambroni. In 1960 he was appointed Minister of Public Works in the Fanfani III Cabinet.
In 1975, Zaccagnini was elected National Secretary of DC, remaining in place until 1980 when he was replaced by Flaminio Piccoli. In 1984 he was elected in the European Parliament. In 1978, during his tenure as national secretary, Democrazia Cristiana's president and Zaccagnini's mentor Aldo Moro was kidnapped by terrorist group Brigate Rosse. The prisoner wrote numerous letters to Zaccagnini, initially invoking his help, then accusing him and other DC leaders of sacrificing him in order to save the new government, which Moro had been instrumental to form.