Wilmington was named by Proprietor Thomas Penn after his friend Spencer Compton, Earl of Wilmington, who was prime minister during the reign of George II of Great Britain.

The area now known as Wilmington was settled by the Lenape (or Delaware Indian) band led by Chief Mattahorn just before Henry Hudson sailed up the Delaware River in 1609. The area was called "Maax-waas Unk" or "Bear Place" after the Maax-waas Hanna (Bear River) that flowed nearby (present-day Christina River). It was called the Bear River because it flowed west to the "Bear People", who are now known as the Susquehannocks.

Adopted in 1899, the Delaware General Corporation Law "reduced restrictions upon corporate action to a minimum" and promised to maintain the most hospitable business enclave in the nation. As a result, nearly 1.5 million companies (including 64% of Fortune 500 firms) are incorporated in Delaware. In fact, a single building located at 1209 North Orange Street in Wilmington serves as the official headquarters of almost 300,000 companies from all over the world, earning the city it's nickname: "Corporate Capital of the World."

In 2017, Wilmington was ranked as the 5th most dangerous city in the U.S. Nearby cities such as Camden, New Jersey and Chester, PA, also ranked in the top 15.

Fort Christina (also called Fort Altena) was the first Swedish settlement in North America and the principal settlement of the New Sweden colony. Built in 1638 and named after Queen Christina of Sweden, it was located approximately 1 mi (1.6 km) east of present-day downtown Wilmington.

The Peoples' Festival is an annual tribute to Bob Marley, who once lived in Wilmington trying to earn money enough to establish his Tuff Gong music studio in Kingston, Jamaica. His son Stephen Marley was born in Wilmington in 1972. Founded in 1994, the festival features reggae and world beat musicians playing original music and Bob Marley and the Wailers songs. The festival is held on the Wilmington riverfront each summer.

Only one small battle was fought in Delaware during the American Revolution, but 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.

DuPont has been headquartered in Wilmington ever since Eleuthère Irénée du Pont, a French Huguenot knowledgeable in the manufacture of gunpowder, emigrated to the United States and founded the company in 1802. The company grew quickly, and by the mid-19th century had become the largest supplier of gunpowder to the United States military, supplying one-third to one-half the powder used by the Union Army during the American Civil War.

The Wilmington Riot of 1968 occurred in April of that year following the assassination of Martin Luther King Jr. The riot did not cause any fatalities, though there were numerous injuries, arrests, and buildings burned. Although the violence was quickly quelled, the governor refused to recall the Delaware Army National Guard, leaving them in the city as an occupying force until the following year, resulting in the longest occupation of an American city by state forces in the nation's history.

Built between 1851 and 1854, the Rockwood Museum was initially the retirement home of Joseph Shipley, a distinguished merchant banker who designed the house to resemble an English country estate. But as anyone who's seen it can attest, the ornate Gothic Revival architecture has all the makings of a classic haunted house--complete with a pet cemetery. Over the years, staff have seen the spirit of a man in a red smoking jacket, the ghost of Shipley's great-niece Mary Bringhurst who was 100 when she died in the home, and the mysterious Shadowman who resides in the basement. The mansion was featured on a season 11 episode of Ghost Hunters.