He worked at a countinghouse in Boston from 1832 to 1834 before studying law and being admitted to the bar. He practiced law with his father in Lexington, Kentucky.
Clay served as chargé d'affaires to Portugal from August 1, 1849, to July 19, 1850. He farmed in Missouri in 1851 and 1852 before returning to Lexington. Clay had been a lifelong member of the Whig Party. But when the Whig Party disintegrated following Henry Clay's death, and due to the controversy surrounding the Kansas–Nebraska Act, Clay joined the Democratic Party. He was elected to the Thirty-fifth Congress (March 4, 1857 – March 3, 1859). Clay did not run for renomion in 1858 and declined an appointment by President James Buchanan to a mission to Germany. His father having died, Clay returned to Lexington and farmed using enslaved labor; his household also included three male boarders.[1] In the 1860 census he owned a dozen slaves in Fayette County (surrounding Lexington).[2]
Clay was a member of the Peace Conference of 1861 held in Washington, D.C., an attempt to prevent the impending American Civil War. During the Civil War Clay supported the Confederacy and was commissioned to raise a regiment. Ill-health from tuberculosis prevented Clay from doing so.
On Clay's service as American chargé d'affaires to Portugal, see Sara B. Bearss, "Henry Clay and the American Claims against Portugal, 1850," Journal of the Early Republic 7 (Summer 1987): 167–80.