The area along the river had been inhabited by various successive cultures of indigenous peoples for thousands of years. At the time of European encounter, historic Native Americans were members of tribes belonging to the [ Eastern Siouan]] family.

The ethnic European and African history of Wilmington spans more than two and a half centuries. In the early 16th century, Italian explorer Giovanni da Verrazzano commitioned by the king of France with a French crew was reportedly the first European to see this area, including the city's present site. The first permanent European settlement in the area started in the 1720s with English colonists. In September 1732, a community was founded on land owned by John Watson on the Cape Fear River, at the confluence of its northwest and northeast branches. The settlement, founded by the first royal governor, George Burrington, was called "New Carthage," and then "New Liverpool;" it gradually took on the name "New Town" or "Newton".Governor Gabriel Johnston soon after established his government there for the North Carolina colony. In 1739 or 1740, the town was incorporated with a new name, Wilmington, in honor of Spencer Compton, Earl of Wilmington.

Some early settlers of Wilmington came from the Albemarle and Pamlico regions, as well as from the colonies of Virginia and South Carolina, but most new settlers migrated from the northern British colonies, the West Indies, and the British Isles. Many of the early settlers were indentured servants, recruited mainly from the British Isles and northern Europe. As the indentured servants gained their freedom and fewer could be persuaded to leave England because of improving conditions there, the colonists imported an increasing number of African slaves to satisfy the labor demand. By 1767, slaves accounted for more than 62% of the population of the Lower Cape Fear region. Many worked in the port as laborers, and some in ship-related trades.

Naval stores and lumber fueled the region's economy, both before and after the American Revolution. During the Revolutionary War, the British maintained a garrison at Fort Johnston near Wilmington.

Due to Wilmington's commercial importance as a major port, it had a critical role in opposition to the British in the years leading up to the Revolution. The city had outspoken political leaders who influenced and led the resistance movement in North Carolina. The foremost of these was Wilmington resident Cornelius Harnett, who served in the General Assembly at the time, where he rallied opposition to the Sugar Act in 1764. When the British Parliament passed the Stamp Act the following year, designed to raise revenue for the Crown with a kind of tax on shipping, Wilmington was the site of an elaborate demonstration against it.

On October 19, 1765, several hundred townspeople gathered in protest of the new law, burned an effigy of one town resident who favored the act, and toasted to "Liberty, Property, and No Stamp Duty." On October 31, another crowd gathered in a symbolic funeral of "Liberty". But before the effigy was buried, Liberty was found to have a pulse, and celebration ensued.

William Houston of Duplin County was appointed stamp receiver for Cape Fear. When Houston visited Wilmington on business, still unaware of his appointment, he recounted,

Governor William Tryon made attempts to mitigate the opposition, to no avail. On November 18, 1765, he pleaded his case directly to prominent residents of the area. They said the law restricted their rights. When the stamps arrived on November 28 on the H.M. Sloop Diligence, Tryon ordered them to be kept on board. Shipping on the Cape Fear River was stopped, as were the functions of the courts.

Tryon, after having received his official commission as governor (a position he had assumed only after the death of Arthur Dobbs), was brought to Wilmington by Captain Constantine Phipps on a barge from the Diligence, and "was received cordially by the gentlemen of the borough." He was greeted with the firing of seventeen pieces of artillery, and the New Hanover County Regiment of the North Carolina militia, who had lined the streets. This "warm welcome" was spoiled, however, after a dispute arose between Captain Phipps and captains of ships in the harbor regarding the display of their colors. The townspeople became infuriated with Phipps and threats were made against both sides. After Tryon harangued them for their actions, the townspeople gathered around the barrels of punch and ox he had brought as refreshments. The barrels were broken open, letting the punch spill into the streets; they threw the head of the ox into the pillory, and gave its body to the slaves. Because of the unrest, Tryon moved his seat of government to New Bern instead of Wilmington.

On February 18, 1766, two merchant ships arrived without stamped papers at Brunswick Town. Each ship provided signed statements from the collectors at their respective ports of origin that there were no stamps available, but Captain Jacob Lobb of the British cruiser Viper seized the vessels. In response, numerous residents from southern counties met in Wilmington. The group organized as the Sons of Liberty and pledged to block implementation of the Stamp Act. The following day, as many as a thousand men, including the mayor and aldermen of Wilmington, were led by Cornelius Harnett to Brunswick to confront Tryon. The governor was unyielding but a mob retrieved the seized ships. They forced royal customs officers and public officials in the region to swear never to issue stamped paper. The Westminster Parliament repealed the Stamp Act in March 1766.

In the 1830s, citizens of Wilmington became eager to take advantage of railroad transportation. Plans were developed to build a railroad line from the capital, Raleigh, to Wilmington. When Raleigh citizens declined to subscribe in sufficient number to stock to raise money for the project, organizers changed the terminus to Weldon. When the railroad line was completed in 1840, it was the longest single line of railroad track in the world. The railroad also controlled a fleet of steamboats that ran between Wilmington and Charleston; these were used both for passenger travel and transportation of freight. Regular boat lines served Fayetteville, and packet lines traveled to northern ports. The city was a main stop-over point, contributing greatly to its commerce.

By mid-century, the churchyard of St. James Episcopal Church and other town cemeteries had become filled with graves. On November 16, 1853, a group of citizens, organized as "The Proprietors of the Wilmington Cemetery," was formed to develop a new cemetery. Sixty-five acres of land around Burnt Mill Creek was chosen as the site for what would be called Oakdale Cemetery. It was the first rural cemetery in North Carolina. The cemetery's first interment, on February 6, 1855, was six-year-old Annie deRosset. Many remains from St. James churchyard were relocated to the new cemetery.

The Wilmington Gas Light Company was established in 1854. Soon after, street lights were powered by gas made from lightwood and rosin, replacing the old street oil lamps. On December 27, 1855, the first cornerstone was laid and construction began on a new City Hall. A grant from the Thalian Association funded the attached opera house, named Thalian Hall. In 1857 the city opened its first public school, named the "Union Free School", on 6th Street between Nun and Church streets, serving white students.

Wilmington had a black majority population before the Civil War. While most were slaves, the city had a significant community of free people of color, who developed businesses and trades. For a period up to Nat Turner's Rebellion, they had been allowed to vote, carry arms and serve in the militia. Fears after the rebellion resulted in the state legislature passing laws to restrict the rights of free blacks.

During the Civil War, the port was the major base for Confederate and privately owned blockade runners, which delivered badly needed supplies from England. The Union mounted a blockade to reduce the goods received by the South. The city was captured by Union forces in the Battle of Wilmington in February 1865, approximately one month after the fall of Fort Fisher had closed the port. As nearly all the military action took place some distance from the city, numerous antebellum houses and other buildings survived the war years.

During the Reconstruction era, former free blacks and newly emancipated freedmen built a community in the city. About 55% of its residents were black people. At the time, Wilmington was the largest city and the economic capital of the state.

Three of the city's aldermen were black. Black people were also in positions of justice of the peace, deputy clerk of court, street superintendent, coroners, policemen, mail clerks and mail carriers.

At the time, black people accounted for over 30% of Wilmington's skilled craftsmen, such as mechanics, carpenters, jewelers, watchmakers, painters, plasterers, plumbers, stevedores, blacksmiths, masons, and wheelwrights. In addition, blacks owned 10 of the city's 11 restaurants and were 90% of the city's 22 barbers. There were more black bootmakers/shoemakers than white ones, and half of the city's tailors were black. Lastly, two brothers, Alexander and Frank Manly, owned the Wilmington Daily Record, one of the few black newspapers in the state, which was reported to be the only black daily newspaper in the country.

In the 1890s, a coalition of Republicans and Populists had gained state and federal offices. The Democrats were determined to reassert their control. There was increasing violence around elections in this period, as armed white paramilitary insurgents, known as Red Shirts, worked to suppress black and Republican voting. White Democrats regained control of the state legislature and sought to impose white supremacy, but some blacks continued to be elected to local offices.

The Wilmington Insurrection of 1898 (formerly and inaccurately called a race riot) occurred as a result of the racially-charged political conflict that had occurred in the decades after the Civil War and efforts by white Democrats to reestablish white supremacy and overturn black voting. In 1898, a cadre of white Democrats, professionals and businessmen, planned to overthrow the city government if their candidates were not elected. Two days after the election, in which a white Republican was elected mayor and both white and black aldermen were elected, more than 1500 white men (led by Democrat Alfred M. Waddell, an unsuccessful gubernatorial candidate in 1896) attacked and burned the only black daily newspaper in the state and ran off the new officers. They overthrew the legitimately-elected municipal government. Waddell and his men forced the elected Republican city officials to resign at gunpoint and replaced them with men selected by leading white Democrats. Waddell was elected mayor by the newly seated board of aldermen that day. Prominent African Americans and white Republicans were banished from the city in the following days. This is the only such coup d'état in United States history.

Whites attacked and killed an estimated 10–100 blacks. No whites died in the violence. As a result of the attacks, more than 2100 blacks permanently left the city, leaving a hole among its professional and middle class. The demographic change was so large that the city became majority white, rather than the majority black it was before the white Democrats' coup.

Following these events, the North Carolina legislature passed a new constitution that raised barriers to voter registration, imposing requirements for poll taxes and literacy tests that effectively disfranchised most black voters, following the example of the state of Mississippi. Blacks were essentially excluded from the political system until after the enactment of the federal Voting Rights Act of 1965.

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

During World War II, Wilmington was the home of the North Carolina Shipbuilding Company. The shipyard was created as part of the U.S. government's Emergency Shipbuilding Program. Workers built 243 ships in Wilmington during the five years the company operated.

Three prisoner-of-war (POW) camps operated in the city from February 1944 through April 1946. At their peak, the camps held 550 German prisoners. The first camp was located on the corner of Shipyard Boulevard and Carolina Beach Road; it was moved downtown to Ann Street, between 8th and 10th avenues, when it outgrew the original location. A smaller contingent of prisoners was assigned to a third site, working in the officers' mess and doing grounds keeping at Bluethenthal Army Air Base, which is now Wilmington International Airport.

The Audubon Trolley Station, Brookwood Historic District, Carolina Heights Historic District, Carolina Place Historic District, City Hall/Thalian Hall, Delgrado School, Federal Building and Courthouse, Fort Fisher, Gabriel's Landing, William Hooper School (Former), Market Street Mansion District, Masonboro Sound Historic District, Moores Creek National Battlefield, Sunset Park Historic District, USS NORTH CAROLINA (BB-55) National Historic Landmark, James Walker Nursing School Quarters, Westbrook-Ardmore Historic District, Wilmington Historic District, and Wilmington National Cemetery are listed on the National Register of Historic Places.

According to 2013 census estimates, there were 112,067 people and 47,003 households in the city. The population density was 2,067.8 people per square mile (714.2/km²)and there were 53,400 housing units. The racial composition of the city was: 73.5% White, 19.9% Black or African American, 6.1% Hispanic or Latino American, 1.2% Asian American, 0.5% Native American, 0.1% Native Hawaiian or other Pacific Islander.

There were 34,359 households, out of which 20.4% had children under the age of 18 living with them, 33.5% were married couples living together, 14.0% had a female householder with no husband present, and 49.5% were non-families. 36.6% of all households were made up of individuals, and 11.3% had someone living alone who was 65 years of age or older. The average household size was 2.10 and the average family size was 2.77.

In the city, the population was spread out, with 18.4% under the age of 18, 17.2% from 18 to 24, 28.5% from 25 to 44, 20.6% from 45 to 64, and 15.3% who were 65 years of age or older. The median age was 34 years. For every 100 females, there were 87.5 males. For every 100 females age 18 and over, there were 85.0 males.

The median income for a household in the city was $31,099, and the median income for a family was $41,891. Males had a median income of $30,803 versus $23,423 for females. The per capita income for the city was $21,503. About 13.3% of families and 19.6% of the population were below the poverty line, including 25.9% of those under age 18 and 12.0% of those age 65 or over.

Less than half of Wilmington's population is religiously affiliated (47.30%), with the majority of practitioners being Christian. The two largest Christian denominations in Wilmington are Protestant: Baptists (14.66%) and Methodists (8.29%), followed by Roman Catholics (7.42%). There are also a significant number of Presbyterians (3.19%), Episcopalians (2.30%), Pentecostals (1.45%), and Lutherans (1.32%). Other Christian denominations make up 7.02%, and the Latter-Day Saints have 0.90%. Much smaller is the proportion of residents who follow Islam (0.46%), and Judaism (0.25%). A small percentage of people practice Eastern religions (0.04%).

Wilmington has significant historical religious buildings, such as the Basilica Shrine of St. Mary and the Temple of Israel.