His success in those assignments led to his election as governor of New York in 1906 in a race with William Randolph Hearst. He was reelected in 1908, though he had repeated clashes with the bosses of the Republican party. He was responsible for setting up two Public Service commissions for curbing race-track gambling and other reforms.

Hughes accepted a seat on the U.S. Supreme Court in 1910 and within a few years became a distinguished member. In 1916, the Republican Party nominated him for president against his wishes and without his consent. Thus, he resigned from the court and made the race against President Woodrow Wilson as a candidate of the Republicans and Progressives, as he believed nobody should decline a nomination for that office. He was soon however led to defeat.

Hughes thus resumed the law practice the next year, and served as chairman of the Draft Appeals Board for New York City. At President Wilson’s request, Hughes also conducted an investigation into charges of inefficiency and scandal in the aircraft industry.

In 1921, Hughes was chosen as the Secretary of State by President Warren G. Harding and took over the problem of making a separate peace with Germany because of the rejection of the Treaty of Versailles. He took efforts to lead the United States into the League of Nations and the World Court, but his efforts were blocked by the Senate. He however succeeded in negotiating an agreement for the limitation in naval armament at the Washington Conference.

His suggestions for easing the reparations burden on Germany led to the Dawes Plan and the Young plan, also bringing a policy of "liquidating imperialism" in Latin America. In 1925, he resigned as Secretary of State and he was appointed as a member of the Permanent Court of International Justice in 1928. He was also head of the American delegations to the Pan American Conference.