Hillis was born on January 28, 1810, in Lexington, Kentucky.
He married Lucinda Maria Starrett in Lafayette, Indiana, on September 30, 1830.
Later that year, Hillis remarried to Esther Ann Auten in Monticello, Illinois, and with her raised seven children.
The Hillis family subsequently moved to Marion County, Iowa, where Jefferson David Hillis was elected to a single term on the Iowa Senate for District 15 between 1852 and 1856 as a Whig.
By the time the American Civil War began, Hillis had moved to Wisconsin and joined a regiment as a military physician.