Born in Dagsboro, Delaware, son of Sarah (née Middleton) and James Clayton. His uncle, Dr. Joshua Clayton, was a former Governor of Delaware and his cousin, Thomas Clayton, was a prominent lawyer, U.S. Senator, and jurist. John M. Clayton studied at Berlin, Maryland and Milford, Delaware when his parents moved there. His boyhood home, known as the Parson Thorne Mansion, was listed on the National Register of Historic Places in 1971. He graduated from Yale University in 1815, studied law at the Litchfield Law School, and in 1819 began the practice of law in Dover, Delaware.