During the Second World War he was a partisan; in collaboration with Arrigo Boldrini, he participated in the liberation of the Romagna.
Zaccagnini was one of the founders of the Christian Democrats and was elected to the Constituent Assembly (1946 ) and in the Chamber of Deputies ( 1948) of the newly formed Italian Republic. He belonged to the Christian Democrat wing, which was a collaboration with the left (or center-left ) parties. In the Chamber of Deputies he remained until in 1979 he was elected to the Senate.
Zaccagnini was Minister of Labour and Social Affairs in 1959 under Antonio Segni and held that office also at the following government headed by Fernando Tambroni at. In the same year (1960 ) he was Minister of Public Works under Amintore Fanfani.
In 1975 he was appointed General Secretary of the Christian Democrats. A post he retained until 1980, he was replaced by Flaminio Piccoli. In 1984 he was elected to the European Parliament.