[2] Bordered by the Mississippi River on the west, the county is named for James Wilkinson, a Revolutionary War military leader and first governor of the Louisiana Territory after its acquisition by the United States in 1803.

After Indian Removal in the 19th century, European-American settlers rapidly developed cotton plantations along the Mississippi River, which forms the western border.

Some planters got wealthy during the antebellum years and built fine mansions in the county seat of Woodville, Mississippi.

Their youngest son, Jefferson Davis, attended the Wilkinson Academy in Woodville for two years before going to Kentucky to another school.

In the early 20th century the boll weevil infestation destroyed much of the cotton crops, and mechanization caused a further loss of agricultural jobs.

Clifton Walker, 37, a married father of five and employee of International Paper Company in Natchez, who was not politically active, was killed in an ambush on Poor House Road near his home.

[5] This lynching cold case has never been solved, although it was among numerous ones that the FBI was investigating since 2007, before the Donald Trump administration ended the effort in 2018.

[1] According to the U.S. Census Bureau, Wilkinson County's racial and ethic makeup was predominantly Black and African American in 2020.

[16] Prior to 1970, when a federal court ruling forced the schools to integrate, the county maintained a separate and highly inferior educational system for Black students.