The North Carolina General Assembly annexed land from the neighboring Duplin County.

Early settlers were Scots-Irish immigrants from Northern Ireland, many came to colonial North Carolina under the protection and inducements of Henry McCulloch, a wealthy London merchant.

The first settlers of the area were Edmond Matthis, William Johnson, William Robinson and John Register, followed by members of the Peterson, Knowles, Vann, Boney, Merritt, Pearson, Powell, Herring, Rogers, Bryant, Blue, Ezzell, James Murphy, Ward, Sellers, Parrish, Fryar, Williamson and Bass families.

In 1745, McCulloch obtained grants from the British Crown covering some 71,160 acres of land "lying and situated on the branches of the North East and Black River.

As an adult, Clinton soon distinguished himself in governmental and military service, serving as Duplin County's Register of Deeds for ten years.

In 1776, at the outbreak of the Revolution, Clinton organized a company of militia from upper Duplin County and led them as captain in the defense of Wilmington against the British.

According to the 2000 census, there were 1,029 members of the state-recognized Coharie Intra-tribal Council, Inc., a state-recognized tribe in Sampson County, who claim "descent from certain tribes of Indians originally inhabiting the coastal regions of North Carolina.

"[4] George Edwin Butler, author of The Croatan Indians of Sampson County, North Carolina.

A Plea for Separate Schools (1916), claimed that the Croatan were mixed-race descendants of English settlers on the Lost Colony of Roanoke Island.

The persons associated as Croatan were variously classified as "White", "Mulatto", "Colored", and "Negro" in the censuses of the 19th century.

No records exist of any English settlement inland of the North Carolina coast prior to 1703, when John Lawson explored the inner region of the territory.

Butler claimed that Lawson had come across Native Americans who were tilling the land in the English style, speaking an antiquated English, having gray and blue eyes, and wanting Lawson to teach them how to "speak from a book" as their forefathers did.

However, far southern areas of Sampson experience only 40–50 days of frost conditions annually, due to its proximity to the Atlantic Ocean.

This was due to the fact that it was the leading center for the Populist Party during the 1890s under local hero Marion Butler – more so indeed than Nash and Chatham counties which had given James B. Weaver a plurality in the 1892 election – and the fact that to compete with the dominant Democratic Party the two would fuse, with the result that after the Populists' demise its adherents turned to the Republicans.

Beginning in 2025, the northwestern areas of Sampson will lie within North Carolina's 7th congressional district, represented by Republican David Rouzer.

After the Civil War, the Naval Stores and timber industries began to lose production value in the county to the lack of cheap labor due to the eradication of slavery among other factors; as a result, subsistence agriculture became the primary industry.

The county has steadily gained stronger manufacturing and services industries since the Civil War.

Manufacturing, agriculture, healthcare, education and retail are the primary sources of employment in the county.

As of 2012, Sampson County is the largest producer of hay and flue-cured tobacco in North Carolina.