In 1906 La Follette entered the U.S. Senate and served until his death. At odds with the conservative leadership of President Taft, La Follette helped found (1911) the National Progressive Republican League; its aim was to wrest the Republican presidential nomination from Taft in 1912 and secure it for La Follette. When Theodore Roosevelt announced his candidacy for the nomination, however, many of La Follette's supporters switched to Roosevelt, who eventually ran on the Progressive party ticket.
In the Senate, La Follette generally supported the reform measures of President Wilson's administration, championing federal railroad regulation, sponsoring (1915) the act that elevated and regulated conditions of maritime employment, and advocating (1913) passage of the Seventeenth Amendment to the U.S. Constitution. He broke with the Wilson administration, however, when he resisted the increasing tendency to side with the Allies; he led the resistance to arming merchant ships and voted against the U.S. declaration of war. He afterward supported war legislation, but made every effort to place the financial burden on the rich. From 1919 to 1925 he was one of the most powerful men in the Senate. He opposed the League of Nations and the Permanent Court of International Justice (the World Court) and fought the U.S. postwar deflation policy. In 1924 he ran for President on the Progressive ticket and polled 5 million votes. The strain of the campaign sapped his strength, and he died the following summer.