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This area at the confluence of rivers was long occupied by successive cultures of indigenous peoples. The Miami tribe established its settlement of Kekionga at the confluence of the Maumee, St. Joseph, and St. Marys rivers. It was the capital of the Miami nation and related Algonquian tribes.

In 1696, Comte de Frontenac appointed Jean Baptiste Bissot, Sieur de Vincennes as commander of the outpost. The French built Fort Miami in 1697 as part of a group of forts and trading posts built between Quebec and St. Louis. In 1721, a few years after Bissot's death, Fort Miami was replaced by Fort St. Philippe des Miamis. The first census in 1744 recorded a population of approximately 40 Frenchmen and 1,000 Miami.

Increasing tension between France and Great Britain developed over control of the territory. In 1760, France ceded the area to Britain after its forces in North America surrendered during the Seven Years' War, known on the North American front as the French and Indian War. In 1763, various Native American nations rebelled against British rule and retook the fort as part of Pontiac's Rebellion. The Miami regained control of Kekionga, ruling it for more than 30 years.

In the Treaty of Paris (1783), which ended the American war for independence, Britain transferred to the new United States its claim of sovereignty over the Northwest Territory—the area north and west of the Ohio River, east of the Mississippi River, and south of British Canada. The Native Americans already living there, though, were not part of that treaty and did not cede their ownership of those lands. American land speculators and pioneers began flooding down the Ohio River into the area, leading to conflict with an alliance of native tribes known as the Western Confederacy. It was headquartered at Kekionga, where the Miami had permitted two refugee tribes dislodged by white homesteaders, the Delaware and the Shawnee, to resettle. The confederacy—which included other Great Lakes and Algonquin tribes as well—began sending war parties to raid settlers, hoping to drive them back across the Appalachian Mountains, and refused to meet for negotiations over a possible treaty to instead cede land for white settlement. The growing violence led to the Northwest Indian War.

In 1790, President George Washington ordered the United States Army to conquer and pacify the tribes. The first expedition, led by General Josiah Harmar reached Kekionga and burned it, but was then driven off by confederacy warriors led by the Miami war chief Little Turtle. The confederacy attacked the second invading force, led in 1791 by General Arthur St. Clair, before it could get that far and wiped it out, in a massacre known as St. Clair's Defeat at modern-day Fort Recovery, Ohio. General Anthony Wayne led a third expedition, defeating the confederacy's warriors at the Battle of Fallen Timbers, near modern-day Toledo, Ohio on August 20, 1794. Wayne's men then marched up the Maumee River, systematically burning evacuated native towns, crops and winter food stores, until they reached its headwaters, where Kekionga was remained in ruins. Wayne ordered Fort Wayne built there to permanently occupy the area.

The following year, Wayne negotiated a peace accord, the Treaty of Greenville with tribal leaders, in which they agreed to stop fighting and ceded most of what is now Ohio along with certain tracts further west, including the area around Fort Wayne encompassing Kekionga and the land portage. Wayne promised the remainder would remain Indian lands, which is why the territory west of Ohio was named Indiana. In subsequent years, the government used Fort Wayne to hand out annual payments under the treaty. But in a recurring cycle, the tribes ran up debts to white traders who came there to sell them alcohol and manufactured goods, and the government pushed tribal leaders—including through bribes—to sell more reservation land to pay off those debts and, when the land was gone, then to agree to have the tribe removed to the Far West.

The first settlement started in 1815. In 1819, the military garrison abandoned the fort and moved to Detroit. In 1822, a federal land office opened to sell land ceded by local Native Americans by the Treaty of St. Mary's in 1818.Platted in 1823 at the Ewing Tavern, the village became an important frontier outpost, and was incorporated as the Town of Fort Wayne in 1829, with a population of 300. The Wabash and Erie Canal's opening improved travel conditions to the Great Lakes and Mississippi River, exposing Fort Wayne to expanded economic opportunities. The population topped 2,000 when the town was incorporated as the City of Fort Wayne on February 22, 1840. Pioneer newspaperman George W. Wood was elected the city's first mayor. Fort Wayne's "Summit City" nickname dates from this period, referring to the city's position at the highest elevation along the canal's route. As influential as the canal was to the city's earliest development, it quickly became obsolete after briefly competing with the city's first railroad, the Pittsburgh, Fort Wayne and Chicago Railway, completed in 1854.

At the turn of the 20th century, the city's population reached nearly 50,000, attributed to a large influx of German and Irish immigrants. Fort Wayne's "urban working class" thrived in industrial and railroad-related jobs. The city's economy was substantially based on manufacturing, ushering in an era of innovation with several notable inventions and developments coming out of the city over the years, such as gasoline pumps (1885), the refrigerator (1913), and in 1972, the first home video game console. A 1913 flood caused seven deaths, left 15,000 homeless, and damaged over 5,500 buildings in the worst natural disaster in the city's history.

As the automobile's prevalence grew, Fort Wayne became a fixture on the Lincoln Highway. Aviation arrived in 1919 with the opening of the city's first airport, Smith Field. The airport served as Fort Wayne's primary commercial airfield until Baer Field (now Fort Wayne International Airport) was transferred to the city in 1947 after serving as a military base during World War II.

Fort Wayne was hit by the Great Depression beginning in 1929, with most factories cutting their workforce. The stock market crash did not discourage plans to build the city's first skyscraper and Indiana's tallest building at the time, the Lincoln Bank Tower. By 1935, the New Deal's WPA put over 7,000 residents back to work through local infrastructure improvements, including the construction of new parks, bridges, viaducts, and a $5.2 million sewage treatment facility.

The post-World War II economic boom helped the city prosper once again. Between 1950 and 1955, more than 5,000 homes were built, many in large subdivisions in rural Allen County. In 1950, Fort Wayne's first bypass, Coliseum Boulevard, opened on the north side of the city, followed by the city's first arena, War Memorial Coliseum, bringing new opportunities for suburban expansion. The Coliseum was home to the NBA's Fort Wayne Pistons from 1952 to 1957. The opening of enclosed shopping malls and the construction of Interstate 69 through rural areas north and west of the city proper further drove the exodus of retail from downtown through the 1960s. According to the Fort Wayne Home Builders Association estimates, more than 80 percent of new home construction occurred outside the city proper in the 1970s.

Like many cities in the Rust Belt, deindustrialization in the 1980s brought urban blight, increased crime, and a decrease in blue-collar manufacturing jobs. Downtown and surrounding neighborhoods continued declining as residents and businesses sprawled further into rural Allen County. A 1982 flood forced an evacuation of 9,000 residents, damaging 2,000 buildings, and costing $56.1 million (1982 USD, $137 million 2015 USD).

The 1990s marked a turnaround for the city, as local leaders focused on crime reduction, economic diversification, and downtown redevelopment. By 1999, Fort Wayne's crime rate decreased to levels not seen since 1974, and the city's economy recovered, with the unemployment rate hovering at 2.4 percent in 1998. Clearing blighted buildings downtown resulted in new public greenspaces, including Headwaters Park, which has become the premier community gathering space and centerpiece in the city's $50 million flood control project. Fort Wayne celebrated its bicentennial in 1994.

The city continued to concentrate on downtown redevelopment and investment in the 2000s. The decade saw the beginnings of its transformation, with renovations and expansions of the Allen County Public Library, Grand Wayne Convention Center, and Fort Wayne Museum of Art. In 2007, the $130 million Harrison Square development was launched, creating Parkview Field. Suburban growth continued, with the opening of Fort Wayne's first lifestyle center, Jefferson Pointe, and the half-billion dollar Parkview Regional Medical Center in 2012.

According to the 2010 Census, there were 420,690 people and 113,541 households. The racial makeup of the city is 73.62% White, 15.41% Black or African American, 0.37% Native American or Alaska Native, 3.3% Asian (1.4% Burmese, 0.4% Indian, 0.3% Vietnamese, 0.2% Chinese, 0.2% Filipino, 0.1% Korean, 0.1% Laotian, 0.1% Thai), 0.06% Pacific Islander, 3.72% from other races, and 3.52% from two or more races. 7.96% of the population are Hispanic or Latino of any race. Among the Hispanic population, 6.1% are Mexican, 0.4% Puerto Rican, and 0.3% Guatemalan.Non-Hispanic Whites were 70.3% of the population in 2010, down from 87.7% in 1970.

There were 101,585 households, of which 30.1% had children under the age of 18 living with them, 42.3% were married couples living together, 14.8% had a female householder with no husband present, 4.9% had a male householder with no wife present, and 38.0% were non-families. 31.2% of all households were made up of individuals, and 9.7% had someone living alone who was 65 years of age or older. The average household size was 2.44 and the average family size was 3.09.

The median age in the city was 34.5 years. 26.4% of residents were under the age of 18; 10.2% were between the ages of 18 and 24; 26.5% were from 25 to 44; 24.9% were from 45 to 64; and 12% were 65 years of age or older. The gender makeup of the city was 48.4% male and 51.6% female.

Fort Wayne has the largest Burmese American population in the U.S., estimated at 6,000. Burmese refugee settlement and "secondary migrants" doubled the city's Asian population between 2000 and 2010.

Fort Wayne is sometimes referred to as the "City of Churches", an unofficial moniker dating to the late-19th century when the city was the regional hub of Catholic, Lutheran, and Episcopal faiths. Today, there are 360 churches in the city. 54 percent of Fort Wayne residents identify as religious, where 16 percent are Catholic, 9 percent are Lutheran, 6.5 percent are Baptist, 5 percent are Methodist, and 0.14 percent are Jewish, with 16.5 percent adhering to other Christian faiths. An increasing religious minority is found among the city's immigrant communities, including Buddhism, Hinduism, and Islam.

Major churches include the Cathedral of the Immaculate Conception, Saint Paul's Evangelical Lutheran Church and Trinity Episcopal Church. Fort Wayne's Reform Judaism population is served by Congregation Achduth Vesholom, the oldest Jewish congregation in Indiana, founded in 1848. In 2013, construction began on the first Burmese Muslim mosque to be built worldwide since the mid-1970s.

As of December 2012, four national Christian denominations were headquartered in the city: the American Association of Lutheran Churches, the Fundamental Baptist Fellowship Association, the Missionary Church and the Fellowship of Evangelical Churches. Fort Wayne is the seat of the Roman Catholic Diocese of Fort Wayne–South Bend, covering 14 counties in Northern Indiana, and the Lutheran Church–Missouri Synod Indiana District, encompassing all of Indiana and north central Kentucky.