Educated as a lawyer, Grandi fought in World War I (1914–18), after which he joined the Fascist squadristi (armed squads that terrorized the countryside). At the national congress of Fascists (Nov. 7, 1921), Grandi made an unsuccessful bid for leadership, losing out to Mussolini.

Grandi participated in the March on Rome that installed Mussolini (Mussolini, Benito) as head of the government (October 1922). He was appointed under secretary of interior in 1924, and in September 1929 he became head of the ministry of foreign affairs. He was named ambassador to Great Britain (July 1932) and concluded an Anglo-Italian agreement (1938) before being recalled to Italy to become minister of justice and president of the Chamber of Fasces and Corporations.

He was opposed to Italy's participation in World War II. Grandi was replaced in the Cabinet in February 1943 but remained chairman of the Grand Council of Fascism. It was at a meeting of this body on the night of July 24–25, 1943, that Grandi attacked Mussolini and proposed a motion of no confidence in him; the council's passage of this resolution effectively deposed Mussolini. Soon afterward, Grandi fled to Lisbon and in 1944 was condemned in absentia to death by a Fascist tribunal in Verona. He later moved to Brazil and eventually returned to Italy to live.