Between the 16th and 19th centuries, most of the land in present-day southern Cobb County belonged to the Cherokee and Creek. Two Native American villages were established near the area that will later become known as Mableton - the settlements of Sweet Water Town and Nickajack. Both tribes coinhabited the area peacefully, with one legend claiming that eventual ownership of the area by the Cherokee was settled via a ball game. One of the early known records of white Europeans being aware of the inhabitants is an 1839 map depicting a 'Nickajack Creek' converging with the Chattahoochee River south and west of the Standing Peachtree settlement.
The town was named after Scottish immigrant Robert Mable (October 18, 1803 – July 7, 1885), who on September 11, 1843, bought 300 acres (approximately 120 hectares or 1.2 km2) of land in southern Cobb County from the Georgia Land Lottery of 1832. Mable was a millwright and farmer who grew cotton, corn, potatoes, and sorghum in the area; he owned between 11 and 48 slaves by 1860. According to oral interviews, Mable was a "fair and kind" enslaver who educated slave children alongside his own, and eventually also liberated his slaves before any government mandate ordered him to. The Robert Mable House and Cemetery, located off U.S. 78 on Floyd Road just north of Clay Road, now includes an amphitheater which hosts public events.
More white settlers moved into the northern edge of Mableton by Nickajack Creek, near Smyrna, in the mid-1800s. They formed a community initially known as Mill Grove and later Nickajack. The creek provided ample power to run grist, saw, cotton, and woolen mills. A covered bridge, originally built c. 1848–1850, traverses the stream and is now part of a historical district. It is one of the few remaining covered bridges in Georgia, and still highly active today after it was later buttressed to handle automobile traffic. A notable resident of the area during that period was John Gann, Cobb County's first state senator. His home, built in 1841, still stands today and is also part of the historical district.
During the Atlanta campaign of the Civil War, Union officers Walter Q. Gresham and Francis P. Blair Jr. of the XVII Corps reached Mableton on July 3, 1864, after the Union defeat at Kennesaw. Gresham replenished his troops' supplies and received medical care at Robert Mable's house, and camped for the night before advancing to Atlanta. The house was spared from the carnage of Sherman's March to the Sea.