Morgenthau was born into a prominent Jewish family in New York City. His father, Henry Morgenthau Sr., was a prominent real estate investor and diplomat who served as ambassador to the Ottoman Empire.

During World War I, Morgenthau worked under Herbert Hoover (who later became US president) in the US Farm Administration of the United States Department of Agriculture. From 1922 to 1933, he was the publisher of American Agriculturist, an independent journal. In 1929, his long-time friend and then governor of New York, Franklin D. Roosevelt, appointed him state commissioner of conservation. Following Roosevelt's election to the presidency, Morgenthau was appointed chairman of the Federal Farm Board (an independent and intergovernmental agency below Cabinet level) in 1933, and, in 1934, secretary of the treasury.

During his eleven years as treasury secretary, Morgenthau stabilized the US dollar, helped finance the “New Deal,” prepared the US economy for war, and financed the war effort through the sale of war bonds. Although he opposed Keynesian economics (a theory, associated with the British economist John Maynard Keynes, that government spending could end the depression) and disagreed with certain aspects of Roosevelt's “New Deal,” he was extremely loyal to Roosevelt.

Morgenthau was the only Jew in Roosevelt's cabinet. While showing some concern for the plight of Germany's Jews, he did not become actively involved in the issue until the late 1930s. In 1938, aware that the US immigration quota system was insufficient to accommodate the number of immigrants who wanted to come to the United States, he proposed to Roosevelt that the United States acquire British and French Guiana in order to use these territories as a place of refuge for immigrants from Nazi Germany. Roosevelt did not favor that particular proposal. Nonetheless, Morgenthau continued to bring various rescue plans to his attention.

In 1943, months after the US State Department confirmed the existence of a German policy and practice aimed at annihilating the Jews of Europe, Morgenthau became involved in the debate over rescue at the urging of some of his staff at Treasury. Disappointed with the lack of tangible results of the Bermuda Conference in the spring of 1943, and suspecting that US State Department officials had delayed issuance of a license to finance the attempt to provide for the relief and evacuation of Jews in France and Romania, Treasury officials John Pehle, Randolph Paul, and Josiah DuBois presented Morgenthau with an 18-page memorandum entitled “Report to the Secretary on the Acquiescence of This Government in the Murder of Jews" on January 13, 1944. Three days later, Morgenthau, Pehle, and Paul met with President Roosevelt. Warning of future negative assessments of the will and actions of Roosevelt administration with respect to trying to rescue European Jews, they urged the president to agree to a more focused effort by the US government to provide relief and, if possible, rescue Jews and non-Jews threatened with death in German-occupied and German-influenced Europe. The president issued an executive order establishing the War Refugee Board (WRB) on January 22, 1944.

Third meeting of the War Refugee Board

During the same year, Morgenthau devised a plan for the occupation of Germany, known as the Morgenthau Plan. It advocated harsh measures to ensure Germany could not go to war again. According to the plan, Germany was to be partitioned into two states, its industry internationalized or annexed by neighboring countries, and its heavy industry dismantled. Although Roosevelt and British Prime Minister Winston Churchill signed a modified version of the plan in September 1944 at the Second Quebec Conference, the victorious Allies never fully implemented it. US Secretary of State Cordell Hull and US Secretary of War Henry Stimson firmly opposed the policy as did British Foreign Secretary Anthony Eden. Moreover, in the first postwar years, the Truman administration's concern about the developing “Cold War” and the need to strengthen the western zones of occupied Germany reinforced opposition to implementation of the Morgenthau Plan.

Still, the western Allies implemented some of its suggestions. For instance, the Morgenthau Plan strongly influenced Joint Chiefs of Staff Directive (JCS 1067), issued on May 10, 1945. This Directive, which remained in force until July 1947, aimed at reducing overall German living standards in order to prevent Germany's reemergence as an aggressive power. It prohibited assistance to the German agricultural sector, and banned the production of oil, rubber, merchant ships, and aircraft.

Due to personal and policy differences with President Harry S. Truman, Morgenthau was forced to resign from the Treasury in July 1945. He spent much of the rest of his life working for Jewish philanthropies, including the United Jewish Appeal, and became a strong supporter of the state of Israel.