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The Catawba Native Americans were the first known historic tribe to settle Mecklenburg County (in the Charlotte area) and were first recorded around 1567 in Spanish records. By 1759 half the Catawba tribe had died from smallpox, which was endemic among Europeans, because the Catawba had not acquired immunity to the new disease. At the time of their largest population, Catawba people numbered 10,000, but by 1826 their total population had dropped to 110.

The European-American city of Charlotte was developed first by a wave of migration of Scots-Irish Presbyterians, or Ulster-Scot settlers from Northern Ireland, who dominated the culture of the Southern Piedmont Region. They made up the principal founding European population in the backcountry. German immigrants also settled the area before the American Revolutionary War, but in much smaller numbers. They still contributed greatly to the early foundations of the region.

Mecklenburg County was initially part of Bath County (1696 to 1729) of New Hanover Precinct, which became New Hanover County in 1729. The western portion of New Hanover split into Bladen County in 1734, its western portion splitting into Anson County in 1750. Mecklenburg County formed from Anson County in 1762. Further apportionment was made in 1792, after the American Revolutionary War, with Cabarrus County formed from Mecklenburg.

In 1842, Union County formed from Mecklenburg's southeastern portion and a western portion of Anson County. These areas were all part of one of the original six judicial/military districts of North Carolina known as the Salisbury District.

The area that is now Charlotte was settled by people of European descent around 1755, when Thomas Spratt and his family settled near what is now the Elizabeth neighborhood. Thomas Polk (granduncle of U.S. President James K. Polk), who later married Thomas Spratt's daughter, built his house by the intersection of two Native American trading paths between the Yadkin and Catawba rivers. One path ran north–south and was part of the Great Wagon Road; the second path ran east–west along what is now Trade Street.

Nicknamed the "Queen City", like its county a few years earlier, Charlotte was named in honor of German princess Charlotte of Mecklenburg-Strelitz, who had become the Queen Consort of Great Britain and Ireland in 1761, seven years before the town's incorporation. A second nickname derives from the American Revolutionary War, when British commander General Charles Cornwallis, 1st Marquess Cornwallis occupied the city but was driven out by hostile residents. He wrote that Charlotte was "a hornet's nest of rebellion", leading to the nickname "The Hornet's Nest".

Within decades of Polk's settling, the area grew to become the Town of Charlotte, incorporating in 1768. Though chartered as Charlotte, the name appears as a form of "Charlottesburgh" on many maps until around 1800. A form of "Charlottetown" also appears on maps of British origin depicting General Cornwallis' route of invasion. The crossroads in the Piedmont became the heart of Uptown Charlotte. In 1770, surveyors marked the streets in a grid pattern for future development. The east–west trading path became Trade Street, and the Great Wagon Road became Tryon Street, in honor of William Tryon, a royal governor of colonial North Carolina. The intersection of Trade and Tryon—commonly known today as "Trade & Tryon", or simply "The Square"—is more properly called "Independence Square".

While surveying the boundary between the Carolinas in 1772, William Moultrie stopped in Charlotte, whose five or six houses were "very ordinary built of logs".

Local leaders came together in 1775 and signed the Mecklenburg Resolves, more popularly known as the Mecklenburg Declaration of Independence. While not a true declaration of independence from British rule, it is among the first such declarations that eventually led to the American Revolution. May 20, the traditional date of the signing of the declaration, is celebrated annually in Charlotte as "MecDec", with musket and cannon fire by reenactors in Independence Square. North Carolina's state flag and state seal also bear the date.

Charlotte is traditionally considered the home of Southern Presbyterianism, but in the 19th century, numerous churches, including Presbyterian, Baptist, Methodist, Episcopal, Lutheran, and Roman Catholic formed, eventually giving Charlotte the nickname, "The City of Churches".

In 1799, in nearby Cabarrus County, 12-year-old Conrad Reed found a 17- pound rock, which his family used as a doorstop. Three years later, a jeweler determined it was nearly solid gold, paying the family a paltry $3.50. The first documented gold find in the United States of any consequence set off the nation's first gold rush. Many veins of gold were found in the area throughout the 19th and early 20th centuries, leading to the 1837 founding of the Charlotte Mint. North Carolina was the chief producer of gold in the United States until the Sierra Nevada find in 1848, although the volume mined in the Charlotte area was dwarfed by subsequent rushes.

Some groups still pan for gold occasionally in local streams and creeks. The Reed Gold Mine operated until 1912. The Charlotte Mint was active until 1861, when Confederate forces seized it at the outbreak of the Civil War. The mint was not reopened at the war's end, but the building, albeit in a different location, now houses the Mint Museum of Art.

The city's first boom came after the Civil War, as a cotton processing center and a railroad hub. Charlotte's city population at the 1880 Census grew to 7,084.

In 1910, Charlotte surpassed Wilmington to become North Carolina's largest city.

The population grew again during World War I, when the U.S. government established Camp Greene, north of present-day Wilkinson Boulevard. Many soldiers and suppliers stayed after the war, launching urbanization that eventually overtook older cities along the Piedmont Crescent. In the 1920 census, Charlotte was only the state's second largest city, Winston-Salem having 48,395, two thousand more people than Charlotte. Charlotte overtook it several years later.

The city's modern-day banking industry achieved prominence in the 1970s and 1980s, largely under the leadership of financier Hugh McColl. McColl transformed North Carolina National Bank (NCNB) into a formidable national bank that through aggressive acquisitions eventually merged with BankAmerica to become Bank of America. First Union, later Wachovia in 2001, experienced similar growth before it was acquired by San Francisco-based Wells Fargo in 2008. Measured by control of assets, Charlotte became the second largest banking headquarters in the United States after New York City.

On September 22, 1989, the city was hit by Hurricane Hugo. With sustained winds of 69 mph (111 km/h) and gusts of 87 mph (140 km/h), Hugo caused massive property damage, destroyed 80,000 trees, and knocked out electrical power to most of the population. Residents were without power for weeks, schools were closed for a week or more, and the cleanup took months. The city was caught unprepared; Charlotte is 200 miles (320 km) inland, and residents from coastal areas in both Carolinas often wait out hurricanes in Charlotte.

In December 2002, Charlotte and much of central North Carolina were hit by an ice storm that resulted in more than 1.3 million people losing power. During an abnormally cold December, many were without power for weeks. Many of the city's Bradford pear trees split apart under the weight of the ice.

In August 2015 and September 2016, the city experienced several days of protests related to the police shootings of Jonathan Ferrell and Keith Scott.

The most recent U.S. Census estimate (2019, released in May 2020) showed 885,708 residents living within Charlotte's city limits and 1,093,901 in Mecklenburg County. The combined statistical area, or trade area, of Charlotte–Concord–Gastonia, NC–SC had a population of 2,728,933. Figures from the more comprehensive 2010 census show Charlotte's population density to be 2,457 per square mile (948.7/km²). There were 319,918 housing units at an average density of 1,074.6 per square mile (414.9/km²).

According to the 2010 United States Census, the racial composition of Charlotte was 45.1% White or Caucasian, 35.0% Black or African American, 13.1% Hispanic or Latin American, 5.0% Asian, 0.5% American Indian, 0.1% Native Hawaiian or Other Pacific Islander, 6.8% some other race, and 2.7% two or more races.

In 1970, the Census Bureau reported Charlotte's population as 30.2% Black and 68.9% White.

The median income for a household in the city was $48,670, and the median income for a family was $59,452. Males had a median income of $38,767 versus $29,218 for females. The per capita income for the city was $29,825. The percentage of the population living at or below the poverty line was 10.6%, with 7.8% of families living at or below the poverty line. Out of the total population, 13.8% of those under the age of 18 and 9.7% of those 65 and older were living below the poverty line.

Charlotte has historically been a Protestant city. It is the birthplace of Billy Graham, and is also the historic seat of Southern Presbyterianism, but the changing demographics of the city's increasing population have brought scores of new denominations and faiths. The Billy Graham Evangelistic Association, Wycliffe Bible Translators' JAARS Center, SIM Missions Organization, and The Christian Research Institute make their homes in the Charlotte general area. In total, Charlotte proper has over 700 places of worship.

The Presbyterian Church (USA) is now the fourth largest denomination in Charlotte, with 68,000 members and 206 congregations. The second largest Presbyterian denomination, the Presbyterian Church in America has 43 churches and 12,000 members, followed by the Associate Reformed Presbyterian Church with 63 churches and 9,500 members.

The Baptist Peace Fellowship of North America is headquartered in Charlotte, and both Reformed Theological Seminary and Gordon-Conwell Theological Seminary have campuses there; more recently, the religious studies academic departments of Charlotte's local colleges and universities have also grown considerably.

The Advent Christian Church is headquartered in Charlotte. The Western North Carolina Annual Conference of the United Methodist Church is also headquartered in Charlotte.

The largest Protestant church in Charlotte, by attendance, is Elevation Church, a Southern Baptist church founded by lead pastor Steven Furtick. The church has over 15,000 congregants at nine Charlotte locations.

Charlotte's Cathedral of Saint Patrick is the seat of the bishop of the Roman Catholic Diocese of Charlotte. The Traditional Latin Mass is offered by the Society of St. Pius X at St. Anthony Catholic Church in nearby Mount Holly. The Traditional Latin Mass is also offered at St. Ann, Charlotte, a church under the jurisdiction of the Roman Catholic Bishop of Charlotte. St. Matthew Parish, located in the Ballantyne neighborhood, is the largest Catholic parish with over 30,000 parishioners. The Greek Orthodox Church's cathedral for North Carolina, Holy Trinity Cathedral, is located in Charlotte.

Charlotte has the largest Jewish population in the Carolinas. Shalom Park in south Charlotte is the hub of the Jewish community, featuring two synagogues, Temple Israel and Temple Beth El, as well as a community center, the Charlotte Jewish Day School for grades K–5, and the headquarters of the Charlotte Jewish News.

Most African Americans in Charlotte are Baptists affiliated with the National Baptist Convention, the largest predominantly African American denomination in the United States. African American Methodists are largely affiliated with either the African Methodist Episcopal Zion Church, headquartered in Charlotte, or the African Methodist Episcopal Church. African American Pentecostals are represented by several organizations such as the United House of Prayer for All People, Church of God in Christ, and the United Holy Church of America.

As of 2013, 51.91% of people in Charlotte practice religion on a regular basis, making it the second most religious city in North Carolina after Winston-Salem. The largest religion in Charlotte is Christianity, with Baptists (13.26%) having the largest number of adherents. The second largest Christian group are the Roman Catholics (9.43%), followed by Methodists (8.02%) and Presbyterians (5.25%). Other Christian affiliates include Pentecostals (2.50%), Lutherans (1.30%), Episcopalians (1.20%), Latter-Day Saints (0.84%), and other Christian (8.87%) churches, including the Eastern Orthodox and non-denominational congregations. Judaism (0.57%) is the second largest religion after Christianity, followed by Eastern religions (0.34%) and Islam (0.32%).