Ephraim McDowell was born in Rockbridge County, Virginia, on November 11, 1771. His father was a veteran of the French and Indian War as well as a colonel during the Revolution. After the family moved to Kentucky the senior McDowell participated in the drafting of the Kentucky Constitution. The young McDowell, interested in medicine, studied at the Seminary of Worley and James and attended lectures in medicine at the University of Edinburgh, Scotland, from 1793 to 1794. Although he did not receive a degree from Edinburgh, he pursued his interest in anatomy and surgery.

McDowell practiced surgery and was a pioneer in abdominal surgical techniques, performing the first ovariotomy in the United States in 1809. One of his most famous patients was James K. Polk, for whom he removed a gall stone and repaired a hernia. McDowell was a member of the Philadelphia Medical Society in 1817 and a founder of Centre College in Danville, Kentucky, in 1819. He was also well known for his generosity, and he performed considerable work for charity.

In June 1830 McDowell was stricken with an acute attack of violent pain, nausea, and fever. He died on June 25, most likely a victim of appendicitis. In 1879 a monument was erected in his honor in Danville. Dr. McDowell was the great great grandfather of General John Campbell Greenway, whose statue was placed in the National Statuary Hall collection by the state of Arizona.