A settlement grew after George Rogers Clark built (1778) a fort as a base of operations against the British and the Native Americans. The city was chartered by the Virginia legislature in 1780, when Kentucky was part of Virginia, and named for Louis XVI of France. Louisville developed as a portage place around the falls (until a canal was built in 1830) and as a river port and major commercial center. Many famous steamboats were constructed there. With the arrival of the railroads in the mid-19th cent., the city became the terminus of both the southern and midwestern rail lines, and shipping expanded significantly. During the Civil War it was a center of pro-Union activity in the state and a military and supply base for federal forces.

The Univ. of Louisville (est. 1798), Bellarmine College, Spalding Univ., and two theological seminaries are there, as is Churchill Downs, a noted racetrack and scene of the annual Kentucky Derby (first held in 1875). The city has many parks and is the site of the state fairgrounds. It has a symphony orchestra and an opera company and hosts an annual festival of new American plays. Among the points of interest are the American Printing House for the Blind; the J. B. Speed Art Museum; the Kentucky Center for the Arts; the Muhammad Ali Center, a museum and cultural-educational center honoring the boxing champion and native; the Actors Theatre of Louisville; Farmington, a historic home (built 1810); the Filson Club, with a historical library and museum; the Jefferson County Courthouse (1850); and Cave Hill Cemetery, where Clark is buried. Nearby are Locust Grove, the last home (1809–18) of Clark, and the Zachary Taylor National Cemetery, the burial place of Zachary Taylor. Fort Knox is in the area.