In 1829 Clayton was elected to the United States Senate as its youngest member. Six years later he declined re-election, but the General Assembly elected him anyway, only to have him resign. He served from March 4, 1829 until December 29, 1836. He distinguished himself in the Senate by a speech during the debate on the Foote resolution, which, though merely relating to the survey of the public lands, introduced into the discussion the whole question of nullification. Clayton favored the extension of the charter for the Second Bank of the United States and his investigation of the Post Office Department led to its reorganization. At various times he served on the Military Affairs, Militia, District of Columbia and Post Office Committees, but his most important position was the Chairmanship of the Judiciary Committee in the 23rd and 24th Congress.