Henry D. Clayton was born in Pulaski County, Georgia. He graduated from Emory and Henry College in Virginia. He moved to Eufaula, Alabama, after graduation and read law. He passed the bar exam in 1849 and opened an office in Clayton, Alabama, where he married Victoria Hunter and raised a family. Two of his sons, Henry De Lamar Clayton, Jr. and Bertram Tracy Clayton, later became United States Congressmen. His brother-in-law James L. Pugh was also a Congressman.