In 1936, following the nomination of then-Governor Alf Landon to run against President Franklin D. Roosevelt, Hamilton was appointed chairman of the Republican National Committee.

[4] Landon lost the election in a landslide, but Hamilton continued as chairman of the Republican National Committee until 1940, due in large part to the considerable help of a freshman Illinois congressman, Everett Dirksen, whose eloquent support turned back several efforts to replace Hamilton.

Hamilton personally visited 3,000 GOP county chairmen during his four-year term, and, in the process, eliminated the huge Landon campaign debt.

When, according to well-established custom, Willkie picked his own national party chairman, Hamilton retired from active politics.

Hamilton received national and international attention in 1950, when he was appointed to represent Harry Gold, a Philadelphia chemist and confessed courier in the Julius and Ethel Rosenberg network that passed atomic secrets to the Soviet Union.