During World War II he acted as partisan, collaborating with Arrigo Boldrini in the liberation of Romagna.

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.

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 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.