Cairo was incorporated as a town on October 28, 1870, and later designated the county seat for Grady County in 1905. It is believed Cairo was named for either the city in Egypt or the town of Cairo, Illinois. The city's name, however, is pronounced "Cayroe". This city has been regarded as Georgia's center for the syrup trade.

Cairo is the birthplace of famous baseball player Jackie Robinson. He was the first African-American baseball player in the major leagues and was named the National League's Most Valuable Player in 1949.