The medical school was housed in several locations during the early 20th century, including the Old State House, the former Arkansas State Capitol, before using funding provided by Franklin D. Roosevelt's Public Works Administration and an Arkansas tax on beer and liquor to build a new campus in 1935 next to the Little Rock City Hospital.

In 1951, Arkansas Governor Sid McMath used cigarette tax funds to construct a new University Hospital and education facilities on a 26-acre site on West Markham Street in what was then the outskirts of Little Rock.

The College of Medicine moved to this location in 1956 when construction on the new University of Arkansas Medical Center was completed and remains there today.

The proximity to the main campus of the University of Arkansas and a rapidly growing region of the state with modern healthcare facilities were promoted as significant benefits to the Northwest Arkansas location, and the official announcement and political campaign for the location began on June 13, 2006.

Phase 2 included additional classrooms, teaching laboratories, and distance learning resources to connect with the Little Rock campus and was completed in 2011.