While in the Senate, he was chairman of the Committee on Claims (Sixty-sixth and Sixty-seventh Congresses) and a member of the Committee on Indian Affairs (Sixty-seventh Congress) and the Committee on Privileges and Elections (Sixty-seventh through Sixty-ninth Congresses). Senator Spencer was also noted for being one of the Republicans in opposition to the Treaty of Versailles and America's participation in the League of Nations, working with Senator Henry Cabot Lodge and the Irreconcilables. Senator Spencer made numerous speeches against the treaty while campaigning for fellow Republicans in 1920 and 1922. Senator Selden P. Spencer died at Walter Reed Hospital in Washington, D.C. on May 16, 1925 following complications from hernia surgery. He is buried in Bellefontaine Cemetery in St. Louis.