Long active in politics and government as a Republican, in 1912 he won a special election to complete the term of Congressman David J. Foster, who had died. He was reelected to a full term in November 1912, and won reelection to four more terms. In 1922, Greene was elected to the United States Senate. He was reelected in 1928, and served until his death. In 1924, Greene was wounded when Prohibition agents attempting to apprehend the owners of a Washington, DC moonshine still accidentally shot him in the head. Greene never fully recovered, and was left partly paralyzed. He died as the result of surgical complications while being treated for a hernia, and was buried in St. Albans.