John Drayton, who was trained as a doctor, held many posts during the Civil War, and at one point he was listed as an acting assistant surgeon on the military staff in Charleston. By 1863, John Drayton was listed as the doctor in attendance on the enslaved people who were detailed to construct Charleston's defenses. Several documents survive from this period showing John's frustration with the Confederate government and their treatment of those conscripted slaves. Eventually he resigned that post, and, as things became more desperate for the South, John was employed as a chemist by the Bureau of Nitre and Mining, supervising enslaved people tasked with manufacturing gun powder. The Confederate government paid Dr. Drayton for his work, and he was stationed at many locations around Charleston throughout the war, including James Island, Bee's Ferry, and Charleston proper.

In 1865 after the end of the Civil War, John moved to Texas where his two other brothers lived. Before he left, however, he set up the first contracts with several companies to mine phosphate at Drayton Hall. His nephew, Charles Henry, took over these contracts when he came of age.