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The Dakota Sioux were the region's sole residents prior to European contact. The city's Dakota name is Bdeóta Othúŋwe ('Many Lakes City'). French explorers arrived in the region in 1680. Gradually, more European-American settlers arrived, competing for game and other resources with the Native Americans. By the Treaty of Paris following the Revolutionary War, British land east of the Mississippi River became part of the United States. In the early 19th century, the US acquired land to the west of the river from France in the Louisiana Purchase. Fort Snelling was built in 1819 by the US Army at the southern edge of present-day Minneapolis, to direct Indian trade away from the British-Canadian traders, and to prevent the Dakota and Ojibwe in the north from fighting each other. The fort attracted traders, settlers and merchants, spurring growth. Agents of the St. Peters Indian Agency built at the fort enforced US policy of assimilating Native Americans into European-American society, asking them to give up hunting for subsistence and to learn to plow for cultivation. The US government pressed the Dakota to sell their land which was ceded in a succession of treaties. The US reneged on the treaties during the Civil War, resulting in hunger, war, internment, and exile of the Dakota from Minnesota.

Outwitting the fort's commandant, Franklin Steele laid his claim on the east bank of Saint Anthony Falls, and John H. Stevens built his home on the west bank. Residents had divergent ideas on names for their community. In 1852, the city's first schoolmaster, Charles Hoag, proposed Minnehapolis, with a silent h, combining the Dakota word for "waterfall", Mníȟaȟa, and the Greek word for "city", polis, which became Minneapolis, meaning 'city of the falls'. The Minnesota Territorial Legislature authorized Minneapolis as a town in 1856, on the Mississippi's west bank. Minneapolis incorporated as a city in 1867 and later joined with the east-bank city of St. Anthony in 1872.

Minneapolis developed around the power source of Saint Anthony Falls, the highest waterfall on the Mississippi River. Forests in northern Minnesota encouraged a lumber industry, which operated seventeen sawmills on power from the waterfall. By 1871, the west river bank had twenty-three businesses, including flour mills, woolen mills, iron works, a railroad machine shop, and mills for cotton, paper, sashes, and planing wood. Due to the occupational hazards of milling, six competitors manufactured artificial limbs by the 1890s. The farmers of the Great Plains grew grain that was shipped by rail to the city's thirty-four flour mills. Millers have used hydropower since the 1st century B.C., but the results in Minneapolis between 1880 and 1930 were described as "the greatest direct-drive waterpower center the world has ever seen." For this half century, Minneapolis led the world in flour milling.

A father of modern milling in America and founder of what became General Mills, Cadwallader C. Washburn revolutionized his business from gristmills to "gradual reduction" by steel and porcelain roller mills capable of producing premium-quality pure white flour very quickly. Some ideas were developed by William Dixon Gray and some say they were acquired through industrial espionage from Hungary by William de la Barre.Charles A. Pillsbury and the C.A. Pillsbury Company across the river were barely a step behind, hiring Washburn employees to immediately use the new methods. The hard red spring wheat that grows in Minnesota became valuable ($0.50 profit per barrel in 1871 increased to $4.50 in 1874), and Minnesota "patent" flour was recognized at the time as the best in the world. Not until later did consumers discover the value in the bran that "...Minneapolis flour millers routinely dumped" into the Mississippi.

A single mill at Washburn-Crosby could make flour for twelve million loaves of bread each day, and by 1900, 14 percent of America's grain was milled in Minneapolis. Further, by 1895, through the efforts of silent partner William Hood Dunwoody, Washburn-Crosby exported four million barrels of flour a year to the United Kingdom. When exports reached their peak in 1900, about one third of all flour milled in Minneapolis was shipped overseas.

The city made changes to rectify discrimination as early as 1886 when Martha Ripley founded Maternity Hospital for both married and unmarried mothers. Known initially as a kindly physician, mayor Doc Ames made his brother police chief, ran the city into corruption, and tried to leave town in 1902.Lincoln Steffens published Ames' story in "The Shame of Minneapolis" in 1903. The gangster Kid Cann engaged in bribery and intimidation from the 1920s until the 1940s.

Bigotry played multiple roles during the early 20th century. In 1910, a Minneapolis developer wrote restrictive covenants based on race and ethnicity into his deeds. Copied by other developers, the practice prevented Asian and African Americans from owning or leasing certain properties. Though such language was prohibited by state law in 1953 and by the federal Fair Housing Act of 1968, restrictive covenants against minorities remained in many Minneapolis deeds as recently as 2017. The Ku Klux Klan succeeded by entering family life, but effectively was a force in the city only from 1921 until 1923. After Minnesota passed a eugenics law in 1925, the proprietors of Eitel Hospital sterilized about one thousand people at the Faribault State Hospital.

From the end of World War I until 1950, Minneapolis was a site of corrosive anti-semitism. A hate group called the Silver Legion of America held meetings in the city around 1936 to 1938. Answering bigotry against Jewish doctors, Mount Sinai Hospital opened in 1948 as the community's first hospital to accept members of minority races and religions on its staff.

When the country's fortunes turned during the Great Depression, the violent Teamsters Strike of 1934 resulted in laws acknowledging workers' rights. A lifelong civil rights activist and union supporter, mayor Hubert Humphrey helped the city establish fair employment practices and a human relations council that interceded on behalf of minorities by 1946. In the 1950s, less than 2 percent of the population was nonwhite.In 1966–1967, years of significant turmoil across the US, bottled-up anger in the black population was released in two disturbances on Plymouth Avenue. A coalition was able to reach a peaceful aftermath but ultimately failed to solve black poverty and unemployment, and a law and order candidate became mayor. Minneapolis contended with white supremacy, participated in desegregation and the civil rights movement, and in 1968 was the birthplace of the American Indian Movement.

Between 1958 and 1963, as part of the most monumental urban renewal plan ever tackled in America, the city razed roughly 40 percent of downtown, destroying the Gateway District and its significant architecture, including the Metropolitan Building. Efforts to save the building failed but sparked interest in historic preservation.

On May 25, 2020, video captured the killing of George Floyd, an African-American man, by a white Minneapolis police officer who knelt on Floyd's neck for several minutes while he struggled to breathe. The incident sparked national unrest, riots, and mass protests.Local protests and riots resulted in extraordinary levels of property damage in Minneapolis, including of a police station that was overrun by demonstrators and set on fire. The Twin Cities experienced prolonged unrest in 2020 and 2021 over racial injustice.

Dakota tribes, mostly the Mdewakanton, were permanent settlers near their sacred site St. Anthony Falls. New settlers arrived during the 1850s and 1860s from New England, New York, Bohemia and Canada, and, during the mid-1860s, immigrants from Finland, Sweden, Norway and Denmark began to call Minneapolis home. Migrant workers from Mexico and Latin America interspersed. Other immigrants came from Germany, Poland, Italy, and Greece. Central European immigrants settled in the Northeast neighborhood, still known for its Czech and Polish cultural heritage. Jews from Central and Eastern Europe, and Russia began arriving in the 1880s and settled primarily on the north side before moving to western suburbs in the 1950s and 1960s. Two groups came for a short while during US government relocations: Japanese during the 1940s, and Native Americans during the 1950s. In 2013, Asians were the state's fastest growing population. Chinese, Japanese and Filipinos came in the 1970s, Hmong, Lao, Cambodian and Vietnamese in the 1970s and 1980s, and people from Tibet, Burma and Thailand came in the 1990s and 2000s. The population of people from India doubled by 2010. After the Rust Belt economy declined during the early 1980s, Minnesota's black population nearly tripled in less than two decades, a large fraction hailing from cities such as Chicago and Gary, Indiana. Black migrants were drawn to Minneapolis (and the Greater Twin Cities) by its abundance of jobs, good schools, and relatively safe neighborhoods. Beginning in the 1990s, a sizable Latino population arrived, along with immigrants from the Horn of Africa, especially Somalia, however immigration of fourteen hundred Somalis in 2016, slowed to forty eight in 2018 under President Trump. In 2015, Brookings characterized Minneapolis as a re-emerging immigrant gateway with about 10 percent foreign-born residents. As of 2019, African Americans make up about one fifth of the city's population.

The US Census Bureau estimates the population of Minneapolis to be 429,606 as of 2019, a 12.3 percent increase since the 2010 census. The population grew until 1950, when the census peaked at 521,718, and then declined until about 1990 as people moved to the suburbs.

As of 2015, Minneapolis had 4 percent adult LGBT residents, roughly the same as the national average. In line with other cities, Human Rights Campaign gave Minneapolis its highest possible score in 2019.

A 2015 report found that racial and ethnic minorities in the city lagged behind white counterparts in education, with 15 percent of blacks and 13 percent of Hispanics holding bachelor's degrees compared to 42 percent of the white population. While the standard of living is rising with incomes among the highest in the Midwest, in 2015 the median household income among minorities was below that of whites by over $17,000 and the poverty rate gap between blacks and whites was the highest in the US. A 2020 study found little change with Minnesota ranking only above the neighboring state of Wisconsin and equal to the states of Iowa, Louisiana, and New Mexico.

Commentators and observers have written about historic racism and socioeconomic disparities in the city. Kirsten Delegard of Mapping Prejudice explained that disparities today evolved from white people asserting control of the city's land. William D. Green of Augsburg said that in Minneapolis the races live in parallel universes.

The Dakota people, the original inhabitants of the area where Minneapolis now stands, believed in the Great Spirit and were surprised that not all European settlers were religious. More than 50 denominations and religions have been established with a Christian majority. Those who arrived from New England were for the most part Protestants, Quakers, and Universalists. The oldest continuously used church, Our Lady of Lourdes Catholic Church, was built in 1856 by Universalists and soon afterward was acquired by a French Catholic congregation. The first Jewish congregation was formed in 1878 as Shaarai Tov, and built Temple Israel in 1928. St. Mary's Orthodox Cathedral was founded in 1887, opened a missionary school, and created the first Russian Orthodox seminary in the US.Edwin Hawley Hewitt designed both St. Mark's Episcopal Cathedral and Hennepin Avenue United Methodist Church just south of downtown. The first basilica in the US, and co-cathedral of the Roman Catholic Archdiocese of Saint Paul and Minneapolis, the Basilica of Saint Mary was named by Pope Pius XI in 1926.

The Billy Graham Evangelistic Association was headquartered in Minneapolis from the late 1940s into the early 2000s.Jim Bakker and Tammy Faye met while attending the Pentecostal North Central University and began a television ministry that by the 1980s reached 13.5 million households. As of 2012, Mount Olivet Lutheran Church in southwest Minneapolis was the nation's second-largest Lutheran congregation, with about 6,000 attendees.Christ Church Lutheran in the Longfellow neighborhood, designed by Eliel Saarinen with an education building by his son Eero Saarinen, is a National Historic Landmark.

During the 1950s, members of the Nation of Islam created a temple in north Minneapolis, and the first Muslim mosque was built in 1967. In 1972 a relief agency resettled the first Shi'a Muslim family from Uganda in the Twin Cities. As of 2017, the 28,000 to 120,000 Somalis who live in the city are primarily Sunni Muslim. The city has about 20 Buddhist and meditation centers. Atheists For Human Rights has its headquarters in the Shingle Creek neighborhood in a geodesic dome. Minneapolis has a body of Ordo Templi Orientis. The first Hindu temple in the city was built in 1978, and North America's largest as of 2010, the Hindu Temple of Minnesota, is in Maple Grove.