Louisville is Kentucky's largest city. It is ranked as either the 17th or 27th largest city in the United States depending on how the population is calculated. The settlement that became the City of Louisville was founded in 1778 by George Rogers Clark and is named after King Louis XVI of France. Louisville is famous as the home of "The Most Exciting Two Minutes in Sports": the Kentucky Derby, the widely watched first race of the Triple Crown of Thoroughbred Racing. Louisville is located at 38° 13' 44"N 085° 44' 58"W / (38.228870, -85.749534).

Louisville is situated in north-central Kentucky on the Kentucky-Indiana border at the only natural obstacle in the Ohio River, the Falls of the Ohio. Louisville is the county seat of Jefferson County, and since 2003, the city's borders are coterminous with those of the county due to merger. Because it includes counties in Southern Indiana, the Louisville metropolitan area is regularly referred to as Kentuckiana. A resident of Louisville is referred to as a Louisvillian. Although situated in a Southern state, Louisville is influenced by both Midwestern and Southern culture, and is commonly referred to as either the northernmost Southern city or the southernmost Northern city in the United States.

Louisville has been the site of many important innovations through history. Notable residents have included inventor Thomas Edison, U.S. Supreme Court Justice Louis Brandeis, boxing legend Muhammad Ali, newscaster Diane Sawyer, actor Tom Cruise, and writers Hunter S. Thompson and Sue Grafton. Notable events occurring in the city include the first public viewing place of Edison's light bulb, the first library open to African Americans in the South, and medical advances including the first human hand transplant, the first self-contained artificial heart transplant, and the development site of the first cervical cancer vaccine.

The first European settlement made in the vicinity of modern-day Louisville was on Corn Island in 1778 by Col. George Rogers Clark. Today, Clark is recognized as the founder of Louisville, and several landmarks are named after him.

Two years later, in 1780, the Virginia General Assembly approved the town charter of Louisville. The city was named in honor of King Louis XVI of France, whose soldiers at the time were aiding Americans in the Revolutionary War. Early residents lived in forts due to Indian raids, but were moving out by the late 1780s. In 1803, explorers Meriwether Lewis and William Clark organized their expedition across America at the Falls of the Ohio in Louisville.

The city attributes its early growth to the fact that river boats had to be unloaded and moved downriver before reaching the falls. By 1828, the population had swelled to 7,000 and Louisville became an incorporated city. The city grew rapidly in its formative years.

Louisville had one of the largest slave trades in the United States before the Civil War and much of the city's initial growth is attributed to that trade. Louisville was the turning point for many enslaved blacks since Kentucky, although it was to be a border state in the Civil War, was nevertheless a slave state and crossing the Ohio River could lead to freedom in the North. Its significant black population and location on the Ohio River resulted in it becoming a stop on the Underground Railroad.

During the Civil War Louisville was a major stronghold of Union forces, which kept Kentucky firmly in the Union. It was the center of planning, supplies, recruiting and transportation for numerous campaigns. By the end of the war, Louisville itself had not been attacked even once, even though surrounded by skirmishes and battles. After 1865 returning Confederate veterans largely took control of the city, leading to the jibe that it joined the Confederacy after the war was over.

The first Kentucky Derby was held on May 17, 1875, at the Louisville Jockey Club track (later renamed to Churchill Downs). The Derby was originally shepherded by Meriwether Lewis Clark, Jr., the grandson of William Clark of the Lewis and Clark Expedition. 10,000 spectators were present at the first Derby to watch Aristides win the race.

On March 27, 1890 the city was devastated and downtown nearly destroyed when an F4 tornado tore through the city at 8:30pm as part of the Mid-Mississippi Valley Tornado Outbreak of March 1890. An estimated 74 to 120 people were killed. The city quickly recovered and signs of the tornado were nearly totally absent within a year.

In late January and February 1937, a month of heavy rain in which 19" fell prompted what became remembered as the "Great Flood of '37". The flood submerged about 70% of the city, power was lost, and it forced the evacuation of 175,000 residents, and also led to fundamental changes in where residents bought houses. Today, the city is protected by numerous flood walls. After the flood, the areas of high elevation in the eastern part of the city saw decades of growth.

Louisville was a center for factory war production during World War II. In May 1942, the U.S. government assigned the Curtiss-Wright Aircraft Company a war plant located at Louisville's air field for wartime aircraft production. The factory produced the C-46 Commando cargo plane, among other aircraft. In 1946 the factory was sold to International Harvester Corporation, which began large-scale production of tractors and agricultural equipment.

Similar to many other older American cities, Louisville began to experience a flight of people and businesses to the suburbs in the 1960s and 1970s. Newly built freeways and interstates helped facilitate this shift. The West End and older areas of the South End in particular began to decline economically as many local factories closed. In 1974 a major (F4) tornado hit Louisville as part of the Super Outbreak of tornadoes that struck 13 states. It covered 21 miles (34 km) and destroyed several hundred homes in the Louisville area but was only responsible for two deaths.

Jefferson County had a population loss of 31,000 from 1970 to 1990, but has since gained 45,000. The population within the old city limits dropped by 134,000 from its peak in 1970, falling from 33rd nationally to 58th, although its population is now stabilizing.

Since the 1980s, many of the city's urban neighborhoods have been revitalized into areas popular with young professionals and college students. The greatest change has occurred along the Bardstown Road corridor, Frankfort Avenue, and the Old Louisville neighborhood. Downtown has also experienced a large amount of growth, including the tripling of its population since 1990, the conversion of waterfront industrial sites into Waterfront Park, and the refurbishing of the former Galleria into the bustling entertainment complex Fourth Street Live.