Nicknamed "the social conscience of the Republican Party," he served as United States Secretary of Labor from 1953 to 1961 during the Eisenhower Administration.

Mitchell was a potential running mate for the 1960 Republican presidential candidate, Vice President Richard M. Nixon.

However, Nixon chose Henry Cabot Lodge Jr. After an unsuccessful run for Governor of New Jersey in 1961, he retired from politics.

When Brehon B. Somerwell went to Washington, D.C. to lead the Army Construction Program, he made Mitchell head of the labor relations division.

After World War II he returned to the private sector; in 1947 he was director for labor relations and operations at Bloomingdale Brothers.

Mitchell encouraged management cooperation, supported labor's right to organize, and sought to improve conditions for marginal workers.

[5] One of Mitchell's aides described his statements against state and national right-to-work laws in 1958 as causing "hell to break loose" in the right-wing of the Republican Party.

After a bitter primary, Mitchell was elected Republican candidate for Governor of New Jersey with 43.7% of the vote, defeating State Senators Walter H. Jones and Wayne Dumont, Jr.

In 1961, he joined the Crown Zellerbach Corporation (at that time an American pulp and paper conglomerate based in San Francisco) as a director and adviser.