As a young Tennessee attorney, Hull early identified with the Democratic Party. He served in the U.S. House of Representatives for 22 years (1907–21, 1923–31) and in the Senate (1931–33). Appointed secretary of state by President Franklin D. Roosevelt (Roosevelt, Franklin D.) at the beginning of the New Deal, he called for a reversal of high tariff barriers that had increasingly stultified U.S. foreign trade since the 19th century. He first won presidential support and public acclaim for such proposals at the inter-American Montevideo Conference (December 1933). He next succeeded in getting Congress to pass the Reciprocal Trade Agreements Act (March 1934), which set the pattern for tariff reduction on a most-favoured-nation basis and was a forerunner to the international General Agreement on Tariffs and Trade (GATT), begun in 1948.

Throughout the 1930s Hull did much to improve the United States' relations with Latin America (Latin America, history of) by implementing what came to be known as the Good Neighbor Policy. At the Montevideo Pan-American Conference (1933) his self-effacing behaviour and acceptance of the principle of nonintervention in the internal affairs of other nations began to counteract the distrust built up through decades of Yankee imperialism in Latin America. He also attended the Pan-American Conference at Buenos Aires (1936) and a special foreign ministers' conference at Havana (1940). Because of the favourable climate of opinion that he had largely created, Hull successfully sponsored a united front of American republics against Axis aggression during World War II.

In East Asia, he rejected a proposed “Japanese Monroe Doctrine” that would have given that country a free hand in China (1934). When Japan served notice later that year that it would not renew the naval-limitation treaties (due to expire in 1936), Hull announced a policy of maintenance of U.S. interests in the Pacific, continuing friendship with China, and military preparedness.

With the outbreak of World War II, Hull and Roosevelt felt that efforts to maintain American neutrality would only encourage aggression by the Axis powers; they therefore decided to aid the Allies. In the crucial negotiations with Japan in the autumn of 1941, Hull stood firm for the rights of China, urging Japan to abandon its military conquests on the mainland.

When the United States entered the war, Hull and his State Department colleagues began planning an international postwar peacekeeping body. At the Moscow Conference of Foreign Ministers (1943)—despite his frail health and advancing age—he obtained a four-nation pledge to continue wartime cooperation in a postwar world organization aimed at maintaining peace and security. For this work, Roosevelt described Hull as the “father of the United Nations,” and universal recognition of his key role came with the Nobel Prize. He resigned after the 1944 presidential election and wrote his Memoirs of Cordell Hull (1950).