He joined the Italian Communist Party (Italian: Partito Comunista Italiano, or PCI) in 1940 and was arrested and tried, but acquitted, for his associations with them.
In the spring of 1943 Giolitti resumed his clandestine activities, for the Communist Party, contacting numerous military and political personalities, in order plan the overthrow of the fascist regime. During World War II, Giolitti was seriously wounded in combat. He was sent to France to recover, and was not able to return to Italy until after the end of the conflict.
After the war, Giolitti was involved in much political activity: he was junior minister to the Foreign minister for Ferruccio Parri's government, communist deputy to the Constituent Assembly, elected to the Chamber of Deputies in the list of PCI in 1948 and 1953. In 1957 he left the Communist Party after the Hungarian uprising and The Manifesto of 101. He then joined the Italian Socialist Party.
Antonio Giolitti was a minister in several Italian governments. He was Minister for the Budget from 1963 to 1964, from 1969 to 1972 and from 1973 to 1974 in the governments led, respectively by Aldo Moro, Mariano Rumor and Emilio Colombo. In this capacity he inspirer the Italian economic planning. From 1977 to 1985, he was a member of the Executive Commission of the European Economic Community in Brussels, and responsible for Regional Policy.
In 1987, Giolitti left the Italian Socialist Party for disagreements with its leader Bettino Craxi. He then returned to the Italian Communist Party (PCI) as an independent candidate and he was elected to the Italian Senate. At the end of the Parliamentary term, he withdrew himself from active politics.
Antonio Giolitti has written political texts and, in 1992, he published a book with his memoirs.
He also participated actively to the Italian cultural activity. In his youth, he was an advisor to the publisher Giulio Einaudi. He collaborated with several cultural magazines, including Lettera Internazionale.