Auguste Chouteau and John Lucas donated land to St. Louis County for a courthouse in 1816. The original courthouse was constructed of brick in the Federal style of architecture and completed in 1828. A second courthouse was designed by architect Henry Singleton, which incorporated the original courthouse as the east wing of the building. The second courthouse was designed with four wings and a dome in the center of its axis. The Old Courthouse underwent a second period of construction beginning in 1851. Due to the extensive remodeling, the original dome, a classic revival style, was replaced. The new dome was of wrought and cast iron with a copper exterior in an Italian Renaissance style, and was designed by William Rumbold. Carl Wimar was commissioned to paint the murals on the interior of the dome. The Old Courthouse was abandoned by the City of St. Louis in 1930. In 1935, St Louis voted a bond issue to raze nearly 40 blocks around the courthouse in the center of St. Louis for the new Jefferson National Expansion Memorial. The courthouse was deeded to the Federal Government in 1940 by the city of St. Louis.

In 1846, slave Dred Scott sued for his freedom in the St Louis County Courthouse based on the fact that he and his wife had lived in the free state of Illinois and the free territory of Wisconsin. The case was ultimately decided by the U.S. Supreme Court in the 1856 case Dred Scott v. Sandford which ruled against Scott. The decision In effect, ruled that slaves had no claim to freedom; they were property and not citizens; and they could not bring suit in federal court.