Wilmington is built on the site of Fort Christina and the settlement Kristinehamn, the first Swedish settlement in North America. The modern city also encompasses other Swedish settlements, such as Timmerön / Timber Island (along Brandywine Creek), Sidoland (South Wellington), Strandviken (along the Delaware River near Simonds Garden) and Översidolandet (along the Christina River, near Woodcrest and Ashley Heights).

The area now known as Wilmington was settled by the Lenape (or Delaware Indian) band led by Sachem (Chief) Mattahorn just before Henry Hudson sailed up the Len-api Hanna ("People Like Me River", present Delaware River) in 1609. The area was called "Maax-waas Unk" or "Bear Place" after the Maax-waas Hanna (Bear River) that flowed by (present Christina River). It was called the Bear River because it flowed west to the "Bear People", who are now known as the People of Conestoga or the Susquehannocks.^{[citation needed]}

The Dutch heard and spelled the river and the place as "Minguannan." When settlers and traders from the Swedish South Company under Peter Minuit arrived in March 1638 on the Fogel Grip and Kalmar Nyckel, they purchased Maax-waas Unk from Chief Mattahorn and built Fort Christina at the mouth of the Maax-waas Hanna (which the Swedes renamed the Christina River after Queen Christina of Sweden). The area was also known as "The Rocks", and is located near the foot of present-day Seventh Street. Fort Christina served as the headquarters for the colony of New Sweden which consisted of, for the most part, the lower Delaware River region (parts of present-day Delaware, Pennsylvania, and New Jersey), but few colonists settled there. Dr. Timothy Stidham (Swedish:Timen Lulofsson Stiddem) was a prominent citizen and doctor in Wilmington. He was born in 1610, probably in Hammel, Denmark and raised in Gothenburg, Sweden. He arrived in New Sweden in 1654 and is recorded as the first physician in Delaware.

The most important Swedish governor was Colonel Johan Printz, who ruled the colony under Swedish law from 1643 to 1653. He was succeeded by Johan Rising, who upon his arrival in 1654, seized the Dutch post Fort Casimir, located at the site of the present town of New Castle, which was built by the Dutch in 1651. Rising governed New Sweden until the autumn of 1655, when a Dutch fleet under the command of Peter Stuyvesant subjugated the Swedish forts and established the authority of the Colony of New Netherland throughout the area formerly controlled by the Swedes. This marked the end of Swedish rule in North America.

Beginning in 1664 British colonization began; after a series of wars between the Dutch and English, the area stabilized under British rule, with strong influences from the Quaker communities under the auspices of Proprietor William Penn. A borough charter was granted in 1739 by King George II, which changed the name of the settlement from Willington, after Thomas Willing (the first developer of the land, who organized the area in a grid pattern similar to that of its northern neighbor Philadelphia), to Wilmington, presumably after the British Prime Minister Spencer Compton, Earl of Wilmington, who took his title from Wilmington, East Sussex in southern England.

Although during the American Revolutionary War only one small battle was fought in Delaware, British troops occupied Wilmington shortly after the nearby Battle of Brandywine on September 11, 1777. The British remained in the town until they vacated Philadelphia in 1778.

In 1800, Eleuthère Irénée du Pont, a French Huguenot, emigrated to the United States. Knowledgeable in the manufacture of gunpowder, by 1802 DuPont had begun making the explosive in a mill on the Brandywine River north of Brandywine Village and just outside the town of Wilmington. The DuPont company became a major supplier to the U.S. military. Located on the banks of the Brandywine River, the village was eventually annexed by Wilmington city.

The greatest growth in the city occurred during the Civil War. Delaware, though officially remaining a member of the Union, was a border state and divided in its support of both the Confederate and the Union causes. The war created enormous demand for goods and materials supplied by Wilmington including ships, railroad cars, gunpowder, shoes, and other war-related goods.

By 1868, Wilmington was producing more iron ships than the rest of the country combined and it rated first in the production of gunpowder and second in carriages and leather. Due to the prosperity Wilmington enjoyed during the war, city merchants and manufacturers expanded Wilmington's residential boundaries westward in the form of large homes along tree-lined streets. This movement was spurred by the first horsecar line, which was initiated in 1864 along Delaware Avenue.

The late 19th century saw the development of the city's first comprehensive park system. William Poole Bancroft, a successful Wilmington businessman influenced by the work of Frederick Law Olmsted, led the effort to establish open parkland in Wilmington. Rockford Park and Brandywine Park were created due to Bancroft's efforts.

Both World Wars stimulated the city's industries. Industries vital to the war effort – shipyards, steel foundries, machinery, and chemical producers – operated around the clock. Other industries produced such goods as automobiles, leather products, and clothing. In desperate need of workers more and more minorities moved to the north and settled in places like Wilmington. This led to tensions that occasionally boiled over like the Wilmington, Delaware race riot of 1919.

The post-war prosperity again pushed residential development further out of the city. In the 1950s, more people began living in the suburbs of North Wilmington and commuting into the city to work. This was made possible by extensive upgrades to area roads and highways and through the construction of Interstate 95, which cut through several of Wilmington's neighborhoods and accelerated the city's population decline. Urban renewal projects in the 1950s and 1960s cleared entire blocks of housing in the Center City and East Side areas.

The Wilmington riot of 1968, a few days after the April 4 assassination of Martin Luther King Jr., became national news. On April 9, Governor Charles L. Terry, Jr. deployed the National Guard and the Delaware State Police to the city at the request of Mayor John Babiarz. Babiarz asked Terry to withdraw the National Guard the following week, but the governor kept them in the city until his term ended in January 1969. This is reportedly the longest occupation of an American city by state forces in the nation's history.

In the 1980s, job growth and office construction were spurred by the arrival of national banks and financial institutions in the wake of the 1981 Financial Center Development Act, which liberalized the laws governing banks operating within the state, and similar laws in 1986. Today, many national and international banks, including Bank of America, Capital One, Chase, and Barclays, have operations in the city, typically credit card operations.

As of the census of 2010, there were 70,851 people, 28,615 households, and 15,398 families residing in the city. The population density was 6,497.6 per square mile (2,508.8/km²). There were 32,820 housing units at an average density of 3,009.9 per square mile (1,162.1/km²) and with an occupancy rate of 87.2%. The racial makeup of the city was 58.0% African American, 32.6% White, 0.4% Native American, 1.0% Asian, <0.1% Pacific Islander, 5.4% from other races, and 2.6% from two or more races. 12.4% of the population were Hispanic or Latino of any race. Non-Hispanic Whites were 27.9% of the population in 2010, compared to 40.5% in 1990. As of the census of 2000, the largest ethnicities included: Irish (8.7%), Italian (5.7%), German (5.2%), English (4.4%), and Polish (3.6%).

There were 28,615 households, out of which 25.0% had children under the age of 18 living with them, 23.5% were married couples living together, 24.8% had a female householder with no husband present, 5.6% had a male householder with no wife present, and 46.2% were non-families. 38.1% of all households were made up of individuals, and 12.3% had someone living alone who was 65 years of age or older. The average household size was 2.36 and the average family size was 3.18.

In the city, the age distribution of the population shows 24.4% under the age of 18, 10.0% from 18 to 24, 29.8% from 25 to 44, 24.2% from 45 to 64, and 11.6% who were 65 years of age or older. The median age was 34.3 years. For every 100 females, there were 90.5 males. For every 100 females age 18 and over, there were 87.4 males.

According to ACS 1-year estimates for 2010, the median income for a household in the city was $32,884, and the median income for a family was $37,352. Males working full-time had a median income of $41,878 versus $36,587 for females working full-time. The per capita income for the city was $24,861. 27.6% of the population and 24.9% of families were below the poverty line. 45.7% of those under the age of 18 and 16.5% of those 65 and older were living below the poverty line.