[4][page needed] Samuel was the 2nd great-grandfather of First Lady Mary Todd Lincoln, making her Ephraim McDowell's great-grandniece.

[5] McDowell received his early education at the classical seminary of Worley and James, then spent three years as a medical student under Dr. Alexander Humphreys in Staunton, Virginia.

He attended lectures in medicine at the University of Edinburgh, Scotland, from 1793 to 1794 and studied privately with John Bell.

[4][page needed] In 1795, McDowell returned from Scotland, settled in Danville, Kentucky, and began his practice as a surgeon.

McDowell perfected the modern surgical technique of lithotomy, for removal of stones obstructing the urinary bladder.

[7] On December 13, 1809, McDowell was called to see Jane Todd Crawford in Green County, Kentucky, 60 miles (97 km) from Danville.

He determined that it would be difficult to remove completely, so he tied a ligature around the fallopian tube near the uterus and cut open the tumor.

[10] As a Presbyterian,[11] McDowell's response to this event was recorded in one of his biographies: How is it that I have been so peculiarly fortunate with my patients of this description?, I know not; for, from all the information I can obtain, there has not one individual survived who has been operated, on elsewhere, for diseased ovaria.

[13] "Having never seen so large a substance extracted, nor heard of an attempt, or success attending any operation such as this required, I gave to the unhappy woman information of her dangerous situation.

It is unclear whether the enslaved women he performed surgeries on gave consent or received sufficient time to recover following the procedure.

[4][page needed] 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 in 1930.

McDowell was a Presbyterian[11] but became an Episcopalian and founded Trinity Episcopal Church in Danville, Kentucky, having donated the land for its first building.