Stimson was born in New York City and graduated from Yale in 1888. After graduate work and law school at Harvard, he entered the law firm headed by Elihu Root in 1891 and two years later became a partner.
In 1906 President of the United States Theodore Roosevelt appointed him U.S. Attorney for the Southern District of New York. Here he made a distinguished record prosecuting antitrust cases. After defeat as Republican candidate for governor of New York in 1910, Stimson was appointed United States Secretary of War in 1911 under William Howard Taft. He continued the reorganization of the Army begun by Elihu Root, bringing it to high efficiency prior to its vast expansion in World War I.
Following the outbreak of war, he was a leader in the American effort to aid the stricken people of Belgium. After the United States became a belligerent, he served in France as an artillery officer reaching rank of Colonel in August 1918.
In 1927, he was sent by President Calvin Coolidge to Nicaragua for civil negotiations. That same year, he was appointed Governor General of the Philippines from 1927 - 1929 (succeeding General Leonard Wood). He opposed Philippine independence, but relaxed existing policies.
From 1929 to 1933 he served as United States Secretary of State under President of the United States Herbert Hoover. In 1929 he shut down MI8, the State Department's cryptanalytic office, saying, "Gentlemen don't read each other's mail."
From 1930 to 1931 Stimson was the Chairman of the U.S. delegation to the London Naval Conference. In the following year, he was the Chairman of the U.S. delegation to the Geneva Disarmament Conference. That same year, the United States issued the "Stimson Doctrine" as a result of Japanese invasion of Manchuria: the United States refused to recognize any situation or treaty that limited U.S. treaty rights or was brought about by aggressive action (formally, action contrary to the Kellogg-Briand Pact).
Returning to private life at the end of President of the United States Herbert Hoover's administration, Stimson was an outspoken advocate of strong opposition to Japanese aggression. In 1941 President of the United States Franklin D. Roosevelt returned him to his old post at the head of the United States Department of War and he skillfully directed the tremendous expansion of the Army to the force of over 10,000,000 men which was successful in World War II. During this period he advised both Roosevelt and Harry S. Truman on the use of atomic weapons, encouraging allowing something short of unconditional surrender for the Japanese, but later supporting the use of the bomb in Hiroshima and Nagasaki.
Stimson retired from public office on 21 September 1945. He died at the age of 83 in Huntington, New York and is buried at Memorial Cemetery near Cold Spring Harbor, Long Island. The United States Navy submarine USS Henry L. Stimson was named in his honor.