The history of Louisville spans hundreds of years, and has been influenced by the area's geography and location.

The rapids at the Falls of the Ohio created a barrier to river travel, and as a result, settlements grew up at this stopping point. The first European settlement in the vicinity of modern-day Louisville was on Corn Island in 1778 by Col. George Rogers Clark, credited as the founder of Louisville. Several landmarks in the community 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 were then aiding Americans in the Revolutionary War. Early residents lived in forts to protect themselves from Indian raids, but moved out by the late 1780s. In 1803, explorers Meriwether Lewis and William Clark organized their expedition across America in the town of Clarksville, Indiana at the present-day Falls of the Ohio opposite Louisville, Kentucky.

The city's early growth was influenced by the fact that river boats had to be unloaded and moved downriver before reaching the falls. By 1828, the population had grown to 7,000 and Louisville became an incorporated city.

Early Louisville was a major shipping port and slaves worked in a variety of associated trades. The city was often a point of escape for slaves to the north, as Indiana was a free state.

During this point in the 1850s, the city was growing and vibrant, but that also came with negativity. It was the center of planning, supplies, recruiting, and transportation for numerous campaigns, especially in the Western Theater. Ethnic tensions rose, and on August 6, 1855, known as "Bloody Monday", Protestant mobs attacked German and Irish Catholic neighborhoods on election day, resulting in 22 deaths and widespread property damage. Then by 1861, the civil war broke out. During the Civil War, Louisville was a major stronghold of Union forces, which kept Kentucky firmly in the Union. By the end of the war, the city of Louisville itself had not been attacked, although skirmishes and battles, including the battles of Perryville and Corydon, took place nearby. After Reconstruction, returning Confederate veterans largely took political control of the city, leading to the jibe that Louisville 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 Churchill Downs). The Derby was originally shepherded by Meriwether Lewis Clark, Jr., the grandson of William Clark of the Lewis and Clark Expedition, and grandnephew of the city's founder George Rogers Clark. Horse racing had a strong tradition in Kentucky, whose Inner Bluegrass Region had been a center of breeding high-quality livestock throughout the 19th century. Ten thousand spectators watched the first Derby, which Aristides won.

On March 27, 1890, the city was devastated and its downtown nearly destroyed when an F4 tornado tore through as part of the middle Mississippi Valley tornado outbreak. It is estimated that between 74 and 120 people were killed and 200 were injured. The damage cost the city $2.5 million (equivalent to $69 million in 2019).

In 1914, the City of Louisville passed a racially-based residential zoning code, following Baltimore, Atlanta, and a handful of cities in the Carolinas. The NAACP challenged the ordinance in two cases. Two weeks after the ordinance enacted, an African-American named Arthur Harris moved into a house on a block designated for whites. He was prosecuted and found guilty. The second case was planned to create a test case. William Warley, the president of the local chapter of the NAACP, tendered a purchase offer on a white block from Charles Buchanan, a white real estate agent. Warley also wrote a letter declaring his intention to build a house on that lot and reside there. With the understanding that the Louisville ordinance made it illegal for him to live there, Warley withheld payment, setting in motion a breach of contract suit by Buchanan. By 1917 the US Supreme Court agreed to hear the case of Buchanan v. Warley. The court struck down the Louisville residential segregation ordinance, ruling that it violated the Fourteenth Amendment's due process clause.

In 1917, shortly after the United States' entry into World War I, Louisville was selected as the site of Camp Zachary Taylor. Camp Taylor was one of the country's largest World War I training camps. It was home of the 84th Infantry Division and trained over 150,000 men by the end of war, including F. Scott Fitzgerald. The camp was closed in 1921. Many of the buildings and infrastructure in the Camp Taylor neighborhood of Louisville are there as a result of the training camp.

In 1929, Louisville completed the lock and dam in the Falls of the Ohio and the city began referring to itself as "where Northern enterprise and Southern hospitality meet". Between the industrial boom of that year and through the Great Depression, Louisville gained 15,000 new residents, about three percent of them black, most fleeing poverty in rural areas.

Throughout January 1937, 19.17 inches (48.7 cm) of rain fell in Louisville, and by January 27, the Ohio River crested at a record 57.15 feet (17.42 m), almost 30 feet (9.1 m) above flood stage. These events triggered the "Great Flood of 1937", which lasted into early February. The flood submerged 60–70 percent of the city, caused complete loss of power for four days, and forced the evacuation of 175,000 or 230,000 residents, depending on sources. Ninety people died as a result of the flood. It led to dramatic changes in where residents lived. Today, the city is protected by numerous flood walls. After the flood, the areas of high elevation in the eastern part of the city had decades of residential 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, which began large-scale production of tractors and agricultural equipment. In 1950, the Census Bureau reported Louisville's population as 84.3% white and 15.6% black.

Throughout the 1940s, there were more black police officers than any other Southern city, though they were allowed to patrol only black districts. This, in part, made Louisville seem like a more racially progressive city than other Southern cities, although only when black citizens accepted a lower status than white citizens. Many historians have referred to this "veil" of segregation as a "polite" racism. Historian George Wright stated that polite racism "often deluded both blacks and well-meaning whites into believing that real progress was being made in their city". For example, in the city Jim Crow practices were not maintained by law so much as by custom.

Similar to many other older American cities, Louisville began to experience a movement of people and businesses to the suburbs in the 1960s and 1970s. Middle class residents used newly built freeways and interstate highways to commute to work, moving into more distant but newer housing. Because of tax laws, businesses found it cheaper to build new rather than renovate older buildings. Economic changes included a decline in local manufacturing. 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 1974 Super Outbreak of tornadoes that struck 13 states. It covered 21 miles (34 km) and destroyed several hundred homes in the Louisville area, causing two deaths.

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/Baxter Avenue and Frankfort Avenue corridors as well as the Old Louisville neighborhood. In recent years, such change has also occurred in the East Market District (NuLu).

Since the late 1990s, Downtown has experienced significant residential, tourist and retail growth, including the addition of major sports complexes KFC Yum! Center and Louisville Slugger Field, conversion of waterfront industrial sites into Waterfront Park, openings of varied museums (see Museums, galleries and interpretive centers below), and the refurbishing of the former Galleria into the bustling entertainment complex Fourth Street Live!, which opened in 2004.

Between the 1970-2000 official US census count, Louisville had been losing population each decade. As of the 2000 census, Louisville had a population of 256,231, down from the 1990 census population of 269,063. Due to the city-county merger that occurred in 2003, which expanded the city limits, the city's population increased to 597,337 at the 2010 census count.

Louisville is the largest city in Kentucky, with 17.1% of the state's total population as of 2010; the balance's percentage was 13.8%. In 2010, over one-third of the population growth in Kentucky was in Louisville's CSA counties.^{[citation needed]}

The 2007 demographic breakdown for the entire Louisville Metro area was 74.8% white (71.7% non-Hispanic), 22.2% black, 0.6% American Indian, 2.0% Asian, 0.1% Hawaiian or Pacific islander, 1.4% other, and 1.6% multiracial. About 2.9% of the total population was identified as Hispanic of any race. During the same year, the area of premerger Louisville consisted 60.1% white, 35.2% African American, 1.9% Asian, 0.2% American Indian, and 3.0% other, with 2.4% identified as Hispanic of any race.

Of the 287,012 households, 29.6% had children under the age of 18 living with them, 45.2% were married couples living together, 14.7% had a female householder with no husband present, and 36.2% were not families. About 30.5% of all households were made up of individuals, and 10.3% had someone living alone who was 65 years of age or older. The average household size was 2.37 and the average family size was 2.97.

The age distribution is 24.3% under the age of 18, 8.9% from 18 to 24, 30.4% from 25 to 44, 22.8% from 45 to 64, and 13.5% who were 65 years of age or older. The median age was 37 years. For every 100 females, there were 91.60 males. For every 100 females age 18 and over, there were 87.60 males.

The median income for a household in 2017 was $51,960. For non-family households the median income was $32,446, and for family households was $67,965. In 2017, males had a median income of $36,326 while females had a median income of $30,464. The latest available data for per capita income comes from 2006, and was $23,304 for the county. About 9.5% of families and 15.1% of the population were below the poverty line in 2017, including 23.5% of those under age 18 and 8.2% of those ages 65 or over.

Louisville hosts religious institutions of various faiths, including Christianity, Judaism, Islam, Hinduism, Buddhism, Sikhism and the Baháʼí Faith.

The 135,421 Roman Catholic Louisvillians are part of the Archdiocese of Louisville, covering 24 counties in central Kentucky, and consisting of 121 parishes and missions spread over 8,124 square miles (21,040 km²). The Cathedral of the Assumption in downtown Louisville is the seat of the Archdiocese of Louisville. Our Lady of Gethsemani Abbey, the monastic home of Catholic writer Thomas Merton, is in nearby Bardstown, Kentucky, and also in the archdiocese. Most of Louisville's Roman Catholic population is of German descent, the result of large-scale 19th-century immigration.

Bellarmine University and Spalding University in Louisville are affiliated with the Roman Catholic Church.

One in three Louisvillians is Southern Baptist, belonging to one of 147 local congregations. This denomination increased in number when large numbers of people moved into Louisville in the early 20th century from rural Kentucky and Tennessee to work in the city's factories; some of these migrants also formed Holiness and Pentecostal churches and Churches of Christ.

German immigrants in the 19th century brought not only a large Catholic population, but also the Lutheran and Evangelical faiths, which are represented today in Louisville by the Evangelical Lutheran Church in America, the Lutheran Church–Missouri Synod, and the United Church of Christ, respectively.

The city is home to two megachurches. Southeast Christian Church, with its main campus in Middletown and three others in the surrounding region, is, as of 2013, the seventh-largest church in the United States.St. Stephen Church is the 38th largest in the US, and has the largest African American congregation in Kentucky.

The city is home to several religious institutions: the Southern Baptist Theological Seminary, Louisville Bible College, Louisville Presbyterian Theological Seminary, and the denominational headquarters of the Presbyterian Church (USA).

The Church of Jesus Christ of Latter-day Saints maintains a temple in suburban Crestwood.

The Jewish population of around 8,500 in the city is served by five synagogues. Most Jewish families emigrated from Eastern Europe at the start of the 20th century; around 800 Soviet Jews have moved to Louisville since 1991. Jewish immigrants founded Jewish Hospital in what was once the center of the city's Jewish district. From 2005 to 2012, Jewish Hospital merged with two Kentucky-based Catholic healthcare systems to form KentuckyOne Health, which later in 2012 announced a partnership with the University of Louisville Hospital. A significant focal point for Louisville's Jewish community is located near Bowman Field, where there are two Orthodox synagogues (including Anshei Sfard, founded in 1893), the Jewish Community Center, Jewish Family and Career Services, and an affordable housing complex.

Since 1996, every May, the Festival of Faiths, a five-day national interfaith gathering, is held featuring music, poetry, film, art and dialogue with internationally renowned spiritual leaders, thinkers and practitioners. The festival is organized by the Center for Interfaith Relations and is held at Actors Theatre of Louisville.

Louisville first welcomed the Baháʼí Faith in 1920. The Spiritual Assembly of the Baháʼí of Louisville was formed in 1944 when their community reached the required amount of nine adult Baháʼís. The first Baháʼí center opened in Louisville in 1967 in Crescent Hill. When the community outgrew the space in 1985, it was sold and another center opened in Buechel in 1998.