The area of Gatlinburg was used for centuries by Native Americans as a footpath, later known as the Indian Gap Trail. The trail took them into the Smokies where an abundance of game could be found. This path also connected the Great Indian Warpath with the Rutherford Indian Trace. The path followed along the banks of the Little Pigeon River into the present day sites of Sevierville, Pigeon Forge, Gatlinburg and the Sugarlands. It crossed the Smokies to the east and entered North Carolina. Today, US highway 441 closely follows the same route.

The first Anglo person known to try to settle the area was William Ogle. Ogle was from Edgefield, South Carolina. He came to the area with the intention of sawing and notching logs for a cabin to be built the following year, when he would bring his family there. Unfortunately, after his return to Edgefield, he was stricken with malaria during the epidemic in the area in 1803. His wife, Martha Jane Huskey Ogle relocated the family to Virginia where she had relatives.

Finally, in 1806, accompanied by her brother, she went to the area near the Little Pigeon River. There, they found the logs that William had cut and notched and proceeded to build a cabin near Baskins Creek and the West Fork of the Little Pigeon River. The cabin still stands today near downtown Gatlinburg.

In the years following the arrival of the Ogles and the Huskeys, the area became known as White Oak Flats. People began to settle in the area, many were former military personnel who were given land grants as partial payment for their service during wartime. Among those were Timothy Reagan, John Ownby, Jr. and Henry Bohanon. Many of their descendants live in the area today.

In 1856 the general store of Radford Gatlin became the site of the new post office and the area became known as Gatlinburg. Gatlin had only lived in the area for four years and his political views combined with an argumentative nature made him a bit unpopular. With talk of a possible civil war going around, Gatlin was one of the very few in the area who sympathized with the Confederacy. Politically, he was directly opposed to most, if not all, his neighbors. About 1857, Gatlin became involved in a feud between his family and the Ogles. He left Gatlinburg in 1859, leaving only his name.

Gatlinburg opposed slavery and in doing so tried to remain neutral in the US Civil War. In an effort to protect the salt peter mines, near the Tennessee-North Carolina border, Colonel William Thomas of the Confederate Army occupied Gatlinbug. The Confederate troops left with the approach of Union forces from Knoxville. For the remainder of the Civil War, Gatlinburg saw only an occasional skirmish.

Following the Civil War, Gatlinburg began to see an upswing in the harvest of timber through the 1880s. A sawmill was established in Gatlinburg in 1900.

Due to the writings of authors like Mary Noailles Murfree and Horace Kephart, tourists began to come see the beauty of the area.

In 1934, the Great Smoky Mountains National Park was established and Gatlinburg has been growing ever since. Today, it is the most frequently visited national park in the United States.