Lodge represented his home state as a Republican in the House of Representatives from 1887 to 1893 and in the Senate from 1893 to 1924. In 1901, he proposed a bill in the Senate that would ban the use of alcohol to minors. As chairman of the Senate Foreign Relations Committee, he led the successful fight against American participation in the League of Nations, which had been proposed by President Woodrow Wilson at the close of World War I.
Lodge maintained that membership in the world peacekeeping organization would threaten the sovereignty of the United States by binding the nation to international commitments it would not or could not keep. Lodge did not object to the United States interfering in other nation's affairs—he was a proponent of imperialism.
Lodge died in 1924 of a stroke at the age of 74. He is interred in the Mount Auburn Cemetery in Cambridge, Massachusetts.
Inscribed autograph while in the U.S. Sentate to “J. Eugene Fowle with the regards of Henry Cabot Lodge June 7, 1915” and matted and framed with a period photograph.