American Indians inhabited the area that became Wilson County for centuries before white and black people moved into the Carolinas. Detailed knowledge of their history and way of life is not known, but in the 17th and 18th centuries, Tuscarora Indians lived in the area of eastern North Carolina that would become Wilson and its surrounding counties. Of Iroquois stock, their name meant Hemp Gatherers.

The earliest European settlers in this area arrived about 1740 but they remained few in number. Most came from Virginia, rather than directly from England or the Carolina coast. At the time of the Revolution the area was still only lightly settled. British troops under General Charles Cornwallis traveled through what would become Wilson County on their trek north from Wilmington to Yorktown during the war.

Wilson County, as established in 1855, measured about thirty miles east to west and twenty miles north to south and contained 373 square miles. It straddled the vague boundary between coastal plain and piedmont. The land was almost level, with slight rolling hills especially to the west and northwest. Streams were narrow and surrounded by swampy land, particularly in the early days. The highest elevation was only 305 feet above sea level, in the northwestern corner of the county, and the lowest point fifty feet above sea level in the extreme southeast of the county. Wilson, both the center of the county and its capital, was about 138 feet above sea level. Tar and turpentine were the principal cash products at the time, with cotton becoming important in the 1860s and tobacco in the 1890s.
 
The railroad was the real making of Wilson in the nineteenth century. By late 1839 the Wilmington and Raleigh Railroad completed the tracks through what would become Wilson County with stops at Bardin's Depot (Black Creek), Toisnot (Wilson), and Joyner's Depot (Elm City). Nine years later, in 1848, Wyatt Moye and Joshua Barnes, both of Edgecombe County, introduce bills in the legislature to "incorporate Toisnot Depot and Hickory Grove, in the County of Edgecombe into a town by the name of Wilson." The town, officially established on January 29, 1849, was named after Louis Dicken Wilson (1789-1847). General Wilson, son of an Edgecombe planter, had been a state Representative for five terms and state Senator for fourteen terms (1820, 1824 to1832, and 1838 to 1846). He organized a company of local volunteers for the Mexican War but died during the war from fever.
Joshua Barnes and his fellow legislators David Williams and George Howard helped incorporated Wilson County six years later from four other counties, Edgecombe, Nash, Wayne, and Johnston. The legislature formally proclaimed Wilson County on 14 February 1855. Wilsonians "had quite a spirited and lively celebration" upon hearing the news. There was a ball with a brass band held on a Thursday night, a party on Friday, and a "Barbecue and public speaking" on Saturday. "A large concourse of ladies and gentlemen from adjoining counties attended."

Elm City is the second largest town in Wilson County. First known as Joyner's Depot, it was chartered as Toisnot in 1873. The railroad changed its name to Elm City, which the town finally accepted in 1913. Stantonsburg in 1817 became the area's first incorporated town. Other Wilson County towns include Black Creek, incorporated in 1870, Saratoga, chartered in 1873 and again in 1899, Lucama, incorporated in 1889, and Sims, chartered in 1913 and incorporated in 1923.

Wilson County did well out of cotton after the Civil War but there were plenty of cotton counties and cotton farmers throughout the South. In 1890 Wilson opened its first tobacco warehouse and by 1920 Wilson was the World's Greatest Tobacco Market. Hackney Brothers established a thriving carriage manufacturing business by the turn of the century. Black entrepreneurs like Samuel Hynes Vick and Charles L. Darden also did well. Barton College, formerly called Atlantic Christian College, opened in 1902 and presently serves an international student body.

After World War II, Wilson County diversified its economy and is now home to large tire and pharmaceutical manufacturers, an array of smaller manufacturers, antique stores, and other commercial and tourist activities as well as tobacco marketing firms.

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