In 1791, Charles Caldwell began to study medicine in the office of Dr. Harris, of Salisbury, N.C., and the following year entered the prestigious Medical Department of the University of Pennsylvania, where his colleagues included Benjamin Rush, William Dewees, and Caspar Wistar. After service with the Army during the Whiskey Rebellion, Caldwell received his medical degree (1796) and took up practice in Philadelphia. Due to strains in his relationship with Rush, Caldwell was never appointed to a professorship at the University, though he did accept a post as instructor in the physical sciences.
In 1819, having already declined to take part in the establishment of medical schools in New York, Baltimore and Philadelphia, Caldwell agreed to help found the Medical Department at Transylvania University in Lexington, Ky. Later, in 1837, he left Transylvania for Louisville, a larger city with greater opportunities, to become the first professor of the Louisville Medical Institute.
Caldwell's research included work on "pestilential" diseases, blood and the circulatory system, and, later in life, physical education and phrenology. As might be expected, his work drew on a strong knowledge of contemporary medical practice, particularly the work of William Cullen and other physicians of the Edinburgh school. He performed a significant role in American medical circles as an importer and translator of foreign medical works, most importantly Blumenbach's Elements of Physiology (1795), and Cullen's First lines of the practice of physic (1815). His own works included Medical & physical memoirs, containing, among other subjects, a particular enquiry into the origin and nature of the late pestilential epidemics of the United States (1801), An experimental inquiry respecting the vitality of the blood (1805), and Phrenology vindicated, and antiphrenology unmasked (1838). Caldwell's autobiography was published in 1855.