The area that would become St. Louis was a center of the Native American Mississippian culture, which built numerous temple and residential earthwork mounds on both sides of the Mississippi River. Their major regional center was at Cahokia Mounds, active from 900 to 1500. Due to numerous major earthworks within St. Louis boundaries, the city was nicknamed as the "Mound City". These mounds were mostly demolished during the city's development. Historic Native American tribes in the area included the Siouan-speaking Osage people, whose territory extended west, and the Illiniwek.

European exploration of the area was first recorded in 1673, when French explorers Louis Jolliet and Jacques Marquette traveled through the Mississippi River valley. Five years later, La Salle claimed the region for France as part of La Louisiane.

The earliest European settlements in the area were built in Illinois Country (also known as Upper Louisiana) on the east side of the Mississippi River during the 1690s and early 1700s at Cahokia, Kaskaskia, and Fort de Chartres. Migrants from the French villages on the opposite side of the Mississippi River (e.g. Kaskaskia) founded Ste. Genevieve in the 1730s.

In 1764, after France lost the Seven Years' War, Pierre Laclède and his stepson Auguste Chouteau founded what was to become the city of St. Louis. (French lands east of the Mississippi had been ceded to Great Britain and the lands west of the Mississippi to Spain; France and Spain were 18th-century allies. Louis XV of France and Charles III of Spain were cousins, both from the House of Bourbon.^{[circular reference]}) The French families built the city's economy on the fur trade with the Osage, as well as with more distant tribes along the Missouri River. The Chouteau brothers gained a monopoly from Spain on the fur trade with Santa Fe. French colonists used African slaves as domestic servants and workers in the city.

France, alarmed that Britain would demand French possessions west of the Mississippi and the Missouri River basin after losing New France to them in 1759–60, transferred these to Spain as part of the Viceroyalty of New Spain. These areas remained in Spanish possession until 1803. In 1780 during the American Revolutionary War, St. Louis was attacked by British forces, mostly Native American allies, in the Battle of St. Louis.

The founding of St. Louis was preceded by a trading business between Gilbert Antoine de St. Maxent and Pierre Laclède (Liguest) in the fall of 1763. St. Maxent invested in a Mississippi River expedition led by Laclède, who searched for a location to base the company's fur trading operations. Though Ste. Genevieve was already established as a trading center, he sought a place less prone to flooding. He found an elevated area overlooking the flood plain of the Mississippi River, not far south from its confluence with the Missouri and Illinois rivers. In addition to having an advantageous natural drainage system, there were nearby forested areas to supply timber and grasslands which could easily be converted for agricultural purposes. This place, declared Laclède, “might become, hereafter, one of the finest cities in America.” He dispatched his 14-year-old stepson, Auguste Chouteau, to the site, with the support of 30 settlers in February 1764.

Laclède arrived at the future town site two months later and produced a plan for St. Louis based on the New Orleans street plan. The default block size was 240 by 300 feet, with just three long avenues running parallel to the west bank of the Mississippi. He established a public corridor of 300 feet fronting the river, but later this area was released for private development.

For the first few years of St. Louis's existence, the city was not recognized by any of the governments. Although the settlement was thought to be under the control of the Spanish government, no one asserted any authority over it, and thus St. Louis had no local government. This vacuum led Laclède to assume civil control, and all problems were disposed in public settings, such as communal meetings. In addition, Laclède granted new settlers lots in town and the surrounding countryside. In hindsight, many of these original settlers thought of these first few years as "the golden age of St. Louis".

By 1765, the city began receiving visits from representatives of the English, French, and Spanish governments. The Indians in the area expressed dissatisfaction at being under the control of British forces. One of the great Ottawa chieftains, Pontiac, was angered by the change of power and the potential for the British to come into their lands. He desired to fight against them but many of the St. Louis inhabitants refused.

St. Louis was transferred to the French First Republic in 1800 (although all of the colonial lands continued to be administered by Spanish officials), then sold by the French to the U.S. in 1803 as part of the Louisiana Purchase. St. Louis became the capital of, and gateway to, the new territory. Shortly after the official transfer of authority was made, the Lewis and Clark Expedition was commissioned by President Thomas Jefferson. The expedition departed from St. Louis in May 1804 along the Missouri River to explore the vast territory. There were hopes of finding a water route to the Pacific Ocean, but the party had to go overland in the Upper West. They reached the Pacific Ocean via the Columbia River in summer 1805. They returned, reaching St. Louis on September 23, 1806. Both Lewis and Clark lived in St. Louis after the expedition. Many other explorers, settlers, and trappers (such as Ashley's Hundred) would later take a similar route to the West.

The city elected its first municipal legislators (called trustees) in 1808. Steamboats first arrived in St. Louis in 1817, improving connections with New Orleans and eastern markets. Missouri was admitted as a state in 1821. St. Louis was incorporated as a city in 1822, and continued to develop largely due to its busy port and trade connections.

Immigrants from Ireland and Germany arrived in St. Louis in significant numbers starting in the 1840s, and the population of St. Louis grew from less than 20,000 inhabitants in 1840, to 77,860 in 1850, to more than 160,000 by 1860. By the mid-1800s, St. Louis had a greater population than New Orleans.

Settled by many Southerners in a slave state, the city was split in political sympathies and became polarized during the American Civil War. In 1861, 28 civilians were killed in a clash with Union troops. The war hurt St. Louis economically, due to the Union blockade of river traffic to the south on the Mississippi River. The St. Louis Arsenal constructed ironclads for the Union Navy.

Slaves worked in many jobs on the waterfront as well as on the riverboats. Given the city's location close to the free state of Illinois and others, some slaves escaped to freedom. Others, especially women with children, sued in court in freedom suits, and several prominent local attorneys aided slaves in these suits. About half the slaves achieved freedom in hundreds of suits before the American Civil War. The printing press of abolitionist Elijah Parish Lovejoy was destroyed for the third time by townsfolk. He was murdered the next year in nearby Alton, Illinois.

After the war, St. Louis profited via trade with the West, aided by the 1874 completion of the Eads Bridge, named for its design engineer. Industrial developments on both banks of the river were linked by the bridge, the second in the Midwest over the Mississippi River after the Hennepin Avenue Bridge in Minneapolis. The bridge connects St. Louis, Missouri to East St. Louis, Illinois. The Eads Bridge became a symbolic image of the city of St. Louis, from the time of its erection until 1965 when the Gateway Arch Bridge was constructed. The bridge crosses the St. Louis riverfront between Laclede's Landing, to the north, and the grounds of the Gateway Arch, to the south. Today the road deck has been restored, allowing vehicular and pedestrian traffic to cross the river. The St. Louis MetroLink light rail system has used the rail deck since 1993. An estimated 8,500 vehicles pass through it daily.

On August 22, 1876, the city of St. Louis voted to secede from St. Louis County and become an independent city. Industrial production continued to increase during the late 19th century. Major corporations such as the Anheuser-Busch brewery and Ralston-Purina company were established. St. Louis also was home to Desloge Consolidated Lead Company and several brass era automobile companies, including the Success Automobile Manufacturing Company; St. Louis is the site of the Wainwright Building, a skyscraper designed in 1892 by architect Louis Sullivan.

The city hosted the 1904 World's Fair and the 1904 Summer Olympics, becoming the first non-European city to host the Olympics. Permanent facilities and structures remaining from the fair are Forest Park and associated structures within its boundaries: the St. Louis Art Museum, the St. Louis Zoo and the Missouri History Museum, as well as Tower Grove Park and the Botanical Gardens.

After the Civil War, social and racial discrimination in housing and employment were common in St. Louis. In 1916, during the Jim Crow Era, St. Louis passed a residential segregation ordinance saying that if 75% of the residents of a neighborhood were of a certain race, no one from a different race was allowed to move in. That ordinance was struck down in a court challenge by the NAACP, so racists invented racial covenants, which prevented the sale of houses in certain neighborhoods to "persons not of Caucasian race". Again, St. Louisans offered a lawsuit in challenge, and such covenants were ruled unconstitutional by the U.S. Supreme Court in 1948 in Shelley v. Kraemer.

In the first half of the 20th century, St. Louis was a destination in the Great Migration of African Americans from the rural South seeking better opportunities. During World War II, the NAACP campaigned to integrate war factories. In 1964, civil rights activists protested at the construction of the Gateway Arch to publicize their effort to gain entry for African Americans into the skilled trade unions, where they were underrepresented. The Department of Justice filed the first suit against the unions under the Civil Rights Act of 1964.

In the first part of the century, St. Louis had some of the worst air pollution in the United States. In April 1940, the city banned the use of soft coal mined in nearby states. The city hired inspectors to ensure that only anthracite was burned. By 1946, the city had reduced air pollution by about three-quarters.

De jure educational segregation continued into the 1950s, and de facto segregation continued into the 1970s, leading to a court challenge and interdistrict desegregation agreement. Students have been bused mostly from the city to county school districts to have opportunities for integrated classes, although the city has created magnet schools to attract students.

St. Louis, like many Midwestern cities, expanded in the early 20th century due to industrialization, which provided jobs to new generations of immigrants and migrants from the South. It reached its peak population of 856,796 at the 1950 census.Suburbanization from the 1950s through the 1990s dramatically reduced the city's population, as did restructuring of industry and loss of jobs. The effects of suburbanization were exacerbated by the small geographical size of St. Louis due to its earlier decision to become an independent city, and it lost much of its tax base. During the 19th and 20th century, most major cities aggressively annexed surrounding areas as residential development occurred away from the central city; however, St. Louis was unable to do so.

Several urban renewal projects were built in the 1950s, as the city worked to replace old and substandard housing. Some of these were poorly designed and resulted in problems. One prominent example, Pruitt-Igoe, became a symbol of failure in public housing, and was torn down less than two decades after it was built.

Since the 1980s, several revitalization efforts have focused on downtown St. Louis.

Urban revitalization continued in the new century. Gentrification has taken place in the Washington Avenue Historic District, Central West End and Forest Park Southeast neighborhoods. This helped St. Louis win the World Leadership Award for urban renewal in 2006. In 2017 the US Census Bureau estimated that St. Louis had a population of 308,826 which is down from a population of 319,371 in 2010.

In the 21st century, the city of St. Louis contains 11% of the total metropolitan population. (The top 20 U.S. metro areas have an average of 24% of their populations in their central cities.) St. Louis grew slightly during the early 2000s, but lost population from 2000 to 2010. Immigration has continued, with the city attracting Vietnamese, Latin Americans predominantly from Mexico, and Bosnians, who make up the largest Bosnian community outside of Bosnia.

St. Louis grew slowly until the American Civil War, when industrialization and immigration sparked a boom. Mid-19th century immigrants included many Irish and Germans; later there were immigrants from southern and eastern Europe. In the early 20th century, African American and white migrants came from the South; the former as part of the Great Migration out of rural areas of the Deep South. Many came from Mississippi and Arkansas.

After years of immigration, migration, and expansion, the city reached its peak population in 1950. That year, the Census Bureau reported St. Louis's population as 82% White and 17.9% African American. After World War II, St. Louis began losing population to the suburbs, first because of increased demand for new housing, unhappiness with city services, ease of commuting by highways, and later, white flight. St. Louis's population decline has resulted in a significant increase of abandoned residential housing units and vacant lots throughout the city proper; this blight has attracted much wildlife (such as deer and coyotes) to the many abandoned overgrown lots.

St. Louis has lost 64.0% of its population since the 1950 United States Census, the highest percent of any city that had a population of 100,000 or more at the time of the 1950 Census. Detroit, Michigan, and Youngstown, Ohio, are the only other cities that have had population declines of at least 60% in the same time frame. The population of the city of St. Louis has been in decline since the 1950 census; during this period the population of the St. Louis Metropolitan Area, which includes more than one county, has grown every year and continues to do so. A big factor in the decline has been the rapid increase in suburbanization.

According to the 2010 United States Census, St. Louis had 319,294 people living in 142,057 households, of which 67,488 households were families. The population density was 5,158.2 people per square mile (1,990.6/km²). About 24% of the population was 19 or younger, 9% were 20 to 24, 31% were 25 to 44, 25% were 45 to 64, and 11% were 65 or older. The median age was about 34 years.

The population was about 49.2% Black, 43.9% White (42.2% Non-Hispanic White), 2.9% Asian, 0.3% Native American/Alaska Native, and 2.4% reporting two or more races. Hispanic or Latino of any race were 3.5% of the population.

The African-American population is concentrated in the north side of the city (the area north of Delmar Boulevard is 94.0% black, compared with 35.0% in the central corridor and 26.0% in the south side of St. Louis). Among the Asian-American population in the city, the largest ethnic group is Vietnamese (0.9%), followed by Chinese (0.6%) and Indians (0.5%). The Vietnamese community has concentrated in the Dutchtown neighborhood of south St. Louis; Chinese are concentrated in the Central West End. People of Mexican descent are the largest Latino group, and make up 2.2% of St. Louis's population. They have the highest concentration in the Dutchtown, Benton Park West (Cherokee Street), and Gravois Park neighborhoods. People of Italian descent are concentrated in The Hill.

In 2000, the median income for a household in the city was $29,156, and the median income for a family was $32,585. Males had a median income of $31,106; females, $26,987. Per capita income was $18,108.

Some 19% of the city's housing units were vacant, and slightly less than half of these were vacant structures not for sale or rent.

In 2010, St. Louis's per-capita rates of online charitable donations and volunteerism were among the highest among major U.S. cities.

As of 2010, 91.05% (270,934) of St. Louis city residents age 5 and older spoke English at home as a primary language, while 2.86% (8,516) spoke Spanish, 0.91% (2,713) Serbo-Croat, 0.74% (2,200) Vietnamese, 0.50% (1,495) African languages, 0.50% (1,481) Chinese, and French was spoken as a main language by 0.45% (1,341) of the population over the age of five. In total, 8.95% (26,628) of St. Louis's population age 5 and older spoke a mother language other than English.

According to a Pew Research study conducted in 2014, 75% of Missourians identify with Christianity and its various denominations, and 4% are adherents of non-Christian religions. 21% have no religion, with 3% specifically identifying as atheists and 3% identifying as agnostics (the other 16% do not identify as "Nothing in particular").

The religious demographics of St. Louis are as follows:

About fifteen families from Bosnia settled in St. Louis between 1960 and 1970. After the Bosnian War started in 1992, more Bosnian refugees began arriving and by 2000, tens of thousands of Bosnian refugees settled in St. Louis with the help of Catholic aid societies. Many of them were professionals and skilled workers who had to take any job opportunity to be able to support their families. Most Bosnian refugees are Muslim, ethnically Bosniaks (87%); they have settled primarily in south St. Louis and South County. Bosnian-Americans are well integrated into the city, developing many businesses and ethnic/cultural organizations.

An estimated 70,000 Bosnians live in the metro area, the largest population of Bosnians in the United States and the largest Bosnian population outside their homeland. The highest concentration of Bosnians is in the neighborhood of Bevo Mill and in Affton, Mehlville, and Oakville of south St. Louis County.