Elected to Parliament in 1909 as Socialist deputy for Mantua, he was expelled from the Socialist Party in 1912 with the reform leader Leonida Bissolati for his moderate, democratic views and for his support for the Libyan war. In response, Bonomi joined the Reformist Socialist group. During World War I he served as a volunteer and became war minister in 1920 in the government of Giovanni Giolitti, negotiating the Treaty of Rapallo between Italy and Yugoslavia. Made prime minister in July 1921, with a coalition government, he was unable to control fascist and socialist excesses and resigned in February 1922, retiring from politics after Benito Mussolini's accession to power. In 1940 he joined the anti-Fascist movement, becoming its leader in 1942. After Mussolini's fall on July 25, 1943, he headed the national committee of anti-Fascist groups and, after the liberation of Rome (June 9, 1944), was designated prime minister by the National Committee of Liberation. The committee, however, soon began to press for a more vigorous policy, and Bonomi resigned on November 26, 1944, only to be reinstated shortly after through the intervention of the British government.

Bonomi laid the foundations of Italy's economic and administrative reconstruction and began the reorganization of the army. On June 12, 1945, he resigned in favour of Ferruccio Parri, but, as chairman of the Constituent Assembly's committee for treaties, he took part in the council of foreign ministers at Paris in 1946. From 1948 until his death he served as president of the Senate.