Walterboro (original spelling: Walterborough) was founded in 1783, as a summer retreat for local planters looking to escape their malaria-ridden, Lowcountry plantations.

Paul's small daughter Mary, was taken ill with malaria; a common disease among the families who had plantations in the marshy areas of the Lowcountry, due to the ground's suitability for rice production.

To prevent Mary from succumbing to the deadly microbe, the Walter brothers went looking for a healthier location in which to live during the summer months, and came to settle the town; with its later being named in their honor.

The town quickly spread from the original Hickory Valley location, after its population experienced a significant increase; this being fueled successively by, the town becoming the county seat in 1821, and the establishment of a railroad line that connected the city with Columbia and Charleston in the 1880s.

After the church was burned down in 1856, and the emancipation of the slaves roughly a decade later, the White community largely left the area.

The Black Catholic community maintained their religion for decades without a priest, before a new church was built for them in the 1890s.

The base was established for the purpose of providing advanced air-combat training, to fighter and bomber groups.

It also hosted the largest camouflage school in the United States, as well as, a 250-person prisoner of war camp.

The establishment of Interstate 95 in the 1960s, made the town a prime overnight stop on the road to Florida or New York.

The southern terminus of U.S. Route 15 is situated in the center of Walterboro; leading northward, running roughly parallel to I-95, reaching St. George in 21 miles (34 km).

According to the United States Census Bureau, Walterboro has a total area of 6.5 square miles (16.8 km2), consisting solely of landmass.

The Lowcountry Regional Airport provides general aviation services to Walterboro and Colleton County.