Established in 1835, the fort served as the U.S. Army headquarters for Cherokee removal (also known as the Trail of Tears) from their ancestral homelands in the Southeast to Indian Territory (present-day Oklahoma).

It housed a garrison of U.S. troops who watched over the largest concentration of internment camps where Cherokee were kept during the summer of 1838 before starting the main trek west to Indian Territory, and served as one of three emigration depots where the Cherokee began their journey west, the others of which were located at Ross's Landing in Chattanooga and Gunter's Landing near Guntersville, Alabama.

The Cherokee population had been spread over a region that included southeast Tennessee, southwest North Carolina, northern Georgia, and northeast Alabama.

Nearby camps stretched for many miles through the valley south of Fort Cass toward present-day Cleveland, Tennessee, including two of which were located at Rattlesnake Springs.

Beginning in 1836, a number of structures were constructed in anticipation of removal operations, including storehouses, cribs, stables, offices, and an armory.

In 1838, Brigadier General Winfield Scott assumed command of the "Army of the Cherokee Nation", headquartered at Fort Cass.

Between the end of August and early December 1838, the Cherokee from Fort Cass and other depots were organized into twelve groups and began the march west.