The town was named for the Mayes family of early settlers after the Wilmington and Manchester Railroad cut through the Mayes' property and began as Mayes Station in 1852, replacing an earlier name of Bradleyville, South Carolina. Fortunes made in cotton and tobacco created wealthy landowners in this area of South Carolina. Mayesville served the local area as a place to process and sell these products and to obtain supplies. Merchants such as I.W. Bradley, Witherspoon Cooper and Isaac Strauss opened some of the earliest businesses in town. The town suffered greatly during the Civil War but thrived again for several decades beginning in about 1880. The patriarch of the Mayes family, Matthew Peterson Mayes II, known as "the Squire," had been a merchant in Raleigh, North Carolina, was wounded in the War of 1812, and then turned to farming. Purchasing an existing plantation prior to 1819, he turned this small beginning into an empire that would survive the Civil War. He died in 1879 and was buried in the historic cemetery at Salem Black River Presbyterian Church. His great-great grandson James Edgar Mayes, known locally as “Bubba Jim" presided over an 8,000-acre cotton plantation in Mayesville and served as president of the National Cotton Council before his death in 1994. His passing was recognized by the South Carolina Legislature. Goodwill Parochial School and Mayesville Historic District are listed on the National Register of Historic Places. The Kineen Hotel is one of the more significant historic buildings still standing.
As of the census of 2000, there were 1,001 people, 331 households, and 246 families residing in the town. The population density was 968.0 people per square mile. There were 369 housing units at an average density of 356.8 per square mile. The racial makeup of the town was 13.19% White, 86.01% African American, 0.10% Native American, 0.30% Asian, 0.10% from other races, and 0.30% from two or more races. Hispanic or Latino of any race were 0.60% of the population. There were 331 households out of which 35.6% had children under the age of 18 living with them, 36.9% were married couplesliving together, 31.4% had a female householder with no husband present, and 25.4% were non-families. 22.1% of all households were made up of individuals and 9.1% had someone living alone who was 65 years of age or older. The average household size was 3.02 and the average family size was 3.60. In the town, the population was spread out with 30.6% under the age of 18, 10.7% from 18 to 24, 25.9% from 25 to 44, 21.1% from 45 to 64, and 11.8% who were 65 years of age or older. The median age was 35 years. For every 100 females, there were 83.7 males. For every 100 females age 18 and over, there were 74.2 males. The median income for a household in the town was $25,852, and the median income for a family was $27,321. Males had a median income of $21,964 versus $20,313 for females. The per capita income for the town was $10,738. About 29.6% of families and 36.5% of the population were below the poverty line, including 49.5% of those under age 18 and 16.2% of those age 65 or over.
