Born into a Jewish family, Mendès-France became a lawyer and was a Radical–Socialist deputy for the Eure département from 1932 to 1940. He was undersecretary of state for finance under Léon Blum from March to June 1938. After serving in the air force in World War II and being imprisoned by the Vichy government, he escaped in June 1941, reached London in February 1942, and joined the Free French air force. From November 1943 to April 1945, he served under General Charles de Gaulle (Gaulle, Charles de), first as commissioner for finance and then as minister of national economy. His austere policies, designed to halt inflation, alienated his colleagues and led to his resignation in April 1945.

A deputy again from June 1946, Mendès-France came to the fore as a severe critic of successive governments' policies on economics, the war in Indochina, and North Africa. After the French were defeated at Dien Bien Phu by the Viet Minh in May 1954, he became premier on the pledge that he would end France's involvement in Indochina within 30 days. His promise was fulfilled at the revitalized Geneva conferences, and an armistice line was drawn between the two halves of Vietnam at the 17th parallel. He then paved the way for Tunisian autonomy and assisted the defeat of the European Defense Community, accepting instead a British plan for German rearmament. Again Mendès-France's policies made him unpopular, and, on Feb. 5, 1955, he was defeated. The immediate cause of his fall was his proposed economic-reform program.

Mendès-France then worked to capture the Radical Party and at first succeeded. He wanted to make the party the centre of the noncommunist left. A leader of the left-centre Front Républicain in the general elections of 1956, he was deputy premier without portfolio in Guy Mollet's government from February to May 1956, when he resigned on Mollet's refusal to adopt a liberal policy in Algeria. Because he opposed de Gaulle's accession to power, Mendès-France was not reelected to the National Assembly in 1958. His influence in the Radical Party declining, he resigned in 1959.

In the presidential election of 1965 he supported François Mitterrand against de Gaulle, and in 1967 he regained his seat in the National Assembly; but he never attracted a substantial group of followers who shared his hostility to the Fifth Republic's presidential government.

Mendès-France published several books on political and economic topics.