The North Carolina General Assembly created Sampson County in April 1784, six months after the Treaty of Paris closed out the Revolutionary War. The new county was carved from Duplin to its east and would later annex land from Wayne and New Hanover. The man pushing for it was Colonel Richard Clinton, a Revolutionary War officer who had helped defend Wilmington from the British. Clinton wanted to honor his stepfather, John Sampson, a Scots-Irish settler who had served as the first Register of Deeds for Duplin County, risen to lieutenant general in the militia, and been elected the first mayor of Wilmington. Sampson had brought Clinton up from boyhood. Clinton proposed the name. The Assembly agreed. The county seat, Clinton, took its founder's name a few years later.

The Coharie are a state-recognized tribe whose ancestors lived in eastern North Carolina long before John Sampson or any European settler arrived. The 2000 census recorded 1,029 enrolled members of the Coharie Intra-tribal Council, headquartered in Clinton. The tribe's heritage center, the Coharie Cultural Center, sits in the western part of the county. In the early 20th century a Clinton attorney named George Edwin Butler published a book claiming that the Coharie - whom he called Croatan - were descended from English settlers of the lost Roanoke colony, citing supposed gray eyes and antiquated English speech. The claim made Butler influential in his time. Modern historians have found no documentary or DNA evidence supporting it. The Coharie identify, as they always have, as Native people, not as the descendants of Walter Raleigh's lost colonists.

For most of the late 19th and early 20th centuries, the South was Democratic - what historians called the Solid South. Sampson County was not. It was one of seven North Carolina counties that voted for Wendell Willkie over Franklin Roosevelt in 1940, and one of fourteen that backed Thomas Dewey over Roosevelt in 1944. The reason ran back to the 1890s, when Sampson was the heartland of North Carolina's Populist Party under the leadership of Marion Butler, born in Sampson County in 1863. Butler served as U.S. senator from 1895 to 1901 on the Populist ticket. After the party collapsed, his followers did not migrate into the dominant Southern Democratic Party - they went to the Republicans. The political memory ran deep enough to keep Sampson voting Republican when almost every other rural Southern county was solidly Democratic, an anomaly that still shows in election maps today.

Agriculture has been the spine of the Sampson economy from the beginning. The earliest industries were naval stores - tar, pitch, turpentine - tapped from longleaf pine forests by enslaved African Americans whose labor built the antebellum economy. After the Civil War the naval stores collapsed and the county shifted to row crops and livestock. Today fully half the land area is in active agriculture. Tobacco, hay, and corn cover the long flat fields. The county leads North Carolina in turkey production. The hog industry, concentrated in confinement operations along the Black River and South River basins, has been controversial - lagoons of waste have at times overflowed during hurricanes, particularly during Floyd in 1999 and Florence in 2018. The county and its farmers continue working through what sustainable agriculture means at this scale. The Black River itself, partly in adjacent Bladen County but draining much of Sampson, holds the oldest documented bald cypress in eastern North America - one tree, by tree-ring dating, more than 2,600 years old.

The list of Sampson natives reads like a strange American almanac. Micajah Autry, a Sampson-born merchant and poet, died at the Alamo in 1836. William Rufus King, born in Sampson in 1786, was elected the thirteenth U.S. vice president in 1852 on a ticket with Franklin Pierce; he died of tuberculosis six weeks after taking the oath in Cuba and never lived to assume office in Washington. John Merrick, born enslaved in Clinton in 1859, moved to Durham and co-founded the North Carolina Mutual Life Insurance Company - for much of the 20th century the largest Black-owned business in the United States. Rufus G. Herring, born in Roseboro, received the Medal of Honor for his actions as a naval reserve officer at Iwo Jima. Lauch Faircloth, born in 1928, served as U.S. senator from 1993 to 1999. Willie Weeks, born in Salemburg in 1947, became one of the most-recorded session bass players in popular music - if you have heard a James Taylor or Eric Clapton album, you have heard Willie Weeks.