After receiving some education in local schools, Clayton spent two years at a classical school. He studied law in Fredericksburg.
Alexander Mosby Clayton was admitted to the Virginia bar in 1823 and practiced in Louisa.
Clayton moved to Clarksville, Tennessee, in the late 1820s. From 1832 to 1834, he served as a federal judge of the Arkansas Territory. In 1837, he moved to Mississippi, where he became a planter and lawyer in Lamar, Marshall (later Benton) County.
He served on the state Supreme Court from 1842 to 1851 but lost his reelection bid in 1851.
From 1844 to 1852 Clayton served as the first president of the Board of Trustees of the University of Mississippi.
In 1850, he espoused the causes of states’ rights and secession. President Franklin Pierce appointed him consul to Havana in 1853, but he resigned in 1854 and returned to Mississippi.
He was a delegate to the Charleston Democratic convention in 1860 and to the Mississippi secession convention in 1861, where he wrote the Secession Ordinance. Clayton also served on the Judiciary and Permanent Constitution Committees of the provisional Confederate Congress. He wrote the provisions making the state governments equal to the federal government, asked for quick ratification of the Constitution, and was instrumental in securing the presidency for Jefferson Davis.
After his service in the provisional Congress, President Davis appointed Clayton judge of the Confederate States court of Mississippi, a position which he retained throughout the Civil War. When the war ended, the Reconstruction government removed him from office. He never again took part in public life.
Clayton espoused the causes of states' rights and secession.
Alexander was married twice, to Mary Talker Thomas in 1826 and to Barbara Anne Barker in 1839.