Stettinius attended but did not graduate from the University of Virginia. He held several jobs before becoming, in 1926, an assistant to a vice president at General Motors; in five years he was himself a vice president of the company. In 1934 he joined U.S. Steel, where he became chairman of the board in 1938.

A year later, Stettinius left private industry to accept appointment as chairman of the War Resources Board. In 1940 he chaired the National Defense Advisory Commission, and in 1941 he assumed the directorship of priorities at the Office of Production Management. Later that year, Stettinius replaced Harry Hopkins in supervising the lend-lease program.

In 1943 Roosevelt appointed Stettinius undersecretary of state, and he succeeded Cordell Hull as secretary the following year. Stettinius dealt effectively with the administrative and personnel functions of his post and soundly implemented Roosevelt's foreign-policy decisions, but he played only a minor role in the formulation of that policy. He did, however, advise Roosevelt during the 1945 Yalta Conference.

A firm believer in a postwar international organization, Stettinius helped lay the groundwork for the United Nations and in 1945 led the U.S. delegation to the San Francisco Conference, which drafted the U.N. Charter.

Two months after Roosevelt's death, President Harry S. Truman appointed James F. Byrnes to replace Stettinius as secretary of state. Stettinius then became the first U.S. delegate to the UN, resigning in 1946. In 1949 he published Roosevelt and the Russians: The Yalta Conference.