The University of Louisville traces its roots to a charter granted in 1798 by the Kentucky General Assembly to establish a school of higher learning in the newly founded town of Louisville. It ordered the sale of 6,000 acres (24 km²) of South Central Kentucky land to underwrite construction, joined on April 3, 1798 by eight community leaders who began local fund raising for what was then known as the Jefferson Seminary. It opened 15 years later and offered college and high school level courses in a variety of subjects. It was headed by Edward Mann Butler from 1813 to 1816, who later ran the first public school in Kentucky in 1829 and is considered Kentucky's first historian.
Despite the Jefferson Seminary's early success, pressure from newly established public schools and media critiques of it as "elitist" would force its closure in 1829.
Eight years later, in 1837, the Louisville City council established the Louisville Medical Institute at the urging of renowned physician and medical author Charles Caldwell. As he had earlier at Lexington's Transylvania University, Caldwell rapidly led LMI into becoming one of the leading medical schools west of the Allegheny Mountains. In 1840, the Louisville Collegiate institute, a rival medical school, was established after an LMI faculty dispute. It opened in 1844 on land near the present day Health sciences campus.