His boyhood home, known as the Parson Thorne Mansion, was listed on the National Register of Historic Places in 1971.

About this time his father died and Clayton became the sole supporter of his immediate family, weekly walking the distance from Dover to Milford to see to their needs.

Conservative in background and outlook, Clayton quickly became a leader of the Adams faction which later developed into the Delaware Whig Party.

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.

[citation needed] After returning to Delaware from his first term in the United States Senate, Clayton was appointed Chief Justice of the Delaware Superior Court, replacing his cousin Thomas Clayton, who had been elected to the vacant U.S. Senate seat.

He served in this position from January 16, 1837, until September 19, 1839, when he resigned to support the presidential candidacy of William Henry Harrison.

Clayton was once again elected to the United States Senate in 1845, where he opposed the annexation of Texas and the Mexican–American War but advocated the active prosecution of the latter once it was begun.

As secretary of state, Clayton was intensely nationalistic and an ardent advocate of commercial expansion but his strict interpretation of international law created crises with Spain, Portugal, and France.

[citation needed] Clayton was again elected to the United States Senate one last time in 1853 and served from March 4, 1853, until his death on November 9, 1856.