European settlement nearly wiped them out — through war, disease, slavery, and oppression — but the Pee Dee Indian Tribe survived. South Carolina officially recognized the tribe around the beginning of the 21st century, and federal recognition has been pursued since 1976. Across the border in present-day Montgomery County, North Carolina, the Town Creek Indian Mound preserves a platform mound and archeological village site of Pee Dee culture, occupied from around AD 1150 to 1400 — about 250 years — and then abandoned for reasons that remain unclear. In 2017, the modern tribe began work on the Pee Dee Tribal Mounds on land in the small Marlboro County town of McColl — a deliberate reconnection with the older sites their ancestors built and lost.

In 1737, the South Carolina Assembly granted 173,000 acres to Welsh settlers — a single, exclusive Welsh Baptist colony along the Pee Dee River. Within a decade, nearly all that land had been taken. The settlers came directly from Wales and from existing Welsh communities in Delaware and Pennsylvania. Between the 1730s and the 1780s, the European population along the Pee Dee from Poston and Gresham, South Carolina, all the way north to McFarlan, North Carolina, was exclusively Welsh. They organized a Baptist church in January 1738. The settlement is one of the most distinctive ethnic colonies in colonial South Carolina — a Welsh-speaking, hymn-singing Baptist community on the South Carolina frontier, deep in territory that had long belonged to the Pee Dee.

On March 12, 1785, the South Carolina General Assembly created Marlboro County under its powers in the 1778 state constitution, written during the American Revolution. The name honored the Duke of Marlborough — an arms-length British honorific that, given the political moment, raises some eyebrows. The new county remained part of Cheraws District until 1798, then became a district itself in 1800. The Reconstruction-era 1868 state constitution converted South Carolina's districts into counties with home rule. The first courthouse was built near the Great Pee Dee River, just north of Crooked Creek, in a village called Carlisle. When Bennettsville was founded in 1819, the legislature designated it as the new county seat. Robert Mills designed the courthouse, completed in 1824.

Marlboro grew on cotton, and on the labor of enslaved people who made cotton profitable. After the Civil War, the brief opening of the Reconstruction era — when Black voters here, as a majority of the county's population, exercised real political power — was closed deliberately by white Democrats who took back state government in the late 19th century. They passed a new state constitution that effectively disenfranchised Black citizens, and they imposed legal segregation and Jim Crow. That arrangement lasted into the 1960s, when the federal Voting Rights Act of 1965 finally gave the federal government enforcement power. The political landscape in Marlboro has shifted significantly since then. African Americans, now a majority of the county again, largely support Democratic candidates. White voters here have moved largely to the Republican side. The county has voted Democratic in most presidential elections since the late 20th century, though by narrowing margins.

Marlboro County remains rural. The 2020 census counted 26,667 people across a county where the Great Pee Dee River, the Little Pee Dee, and Crooked Creek all carve through farmland and pine flatwoods. Lake Wallace and Lake Paul Wallace offer fishing and boating; Lake Paul Wallace Wildlife Management Area protects the surrounding habitat. The major employers — the federal Department of Justice (via the Bennettsville prison), Domtar, Food Lion, Domino's, and Walmart — give some sense of the modern economy. The towns are small: Bennettsville is the largest, followed by Blenheim, Clio, McColl, and Tatum. Cheraw sits mostly across the line in Chesterfield. The county's identity remains tied to the river that the Pee Dee named, the duke who never saw it, and the Welsh Baptists whose hymns once echoed along its banks.