Hopkins was born at 512 Tenth Street in Sioux City, Iowa, the fourth child of four sons and one daughter of David Aldona and Anna (nee Pickett) Hopkins. His father, born in Bangor, Maine, ran a harness shop (after an erratic career as a salesman, prospector, storekeeper and bowling-alley operator), but his real passion was bowling, and he eventually returned to it as a business. Anna Hopkins, born in Hamilton, Ontario, had moved at an early age to Vermillion, South Dakota, where she married David. She was deeply religious and active in the affairs of the Methodist church.

In 1915, New York City Mayor John Purroy Mitchel appointed Hopkins executive secretary of the Bureau of Child Welfare which administered pensions to mothers with dependent children.  Hopkins at first opposed America's entrance into World War I, but, when war was declared in 1917, he supported it enthusiastically. He was rejected for the draft because of a bad eye. Hopkins moved to New Orleans where he worked for the American Red Cross as director of Civilian Relief, Gulf Division. Eventually, the Gulf Division of the Red Cross merged with the Southwestern Division and Hopkins, headquartered now in Atlanta, was appointed general manager in 1921. Hopkins helped draft a charter for the American Association of Social Workers (AASW) and was elected its president in 1923.  In 1922, Hopkins returned to New York City, where the AICP was involved with the Milbank Memorial Fund and the State Charities Aid Association in running three health demonstrations in New York State. Hopkins became manager of the Bellevue-Yorkville health project and assistant director of the AICP. In mid-1924 he became executive director of the New York Tuberculosis Association. During his tenure, the agency grew enormously and absorbed the New York Heart Association.  In 1931, New York Governor Franklin D. Roosevelt named R. H. Macy's department store president Jesse Straus as president of the Temporary Emergency Relief Administration (TERA). Straus named Hopkins, then unknown to Roosevelt, as TERA's executive director. His efficient administration of the initial $20 million outlay to the agency gained Roosevelt's attention, and in 1932, he promoted Hopkins to the presidency of the agency. Hopkins and Eleanor Roosevelt began a long friendship, which strengthened his role in relief programs.

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