[2] During the 1850s, the arrival of the railroad— namely the East Tennessee, Virginia and Georgia Railroad and its predecessor lines— transformed Knoxville from a small river town of just over 2,000 residents to one of the southeast's major wholesaling centers.

Wholesaling firms built dozens of large warehouses along Jackson Avenue and adjacent streets, where smalltown merchants from across East Tennessee would purchase goods and supplies to resell at rural general stores.

The railyard, which consists of eleven parallel tracks at its widest point, stretches from Broadway on the southwest to Central Street on the northeast.

The Old City, a neighborhood that developed along with the railroad in the latter half of the 19th century, is concentrated around the intersection of Central Street and Jackson Avenue.

Mountain barriers were an impediment to economic development in East Tennessee throughout the first half of the 19th century, and as early as the 1830s, Knoxville's leaders considered the railroad a solution to this isolation.

Among the earliest proposals was the Hiwassee Railroad, conceived by several Athens, Tennessee-based businessmen, which would connect Knoxville with the Charleston and Hamburg line in Dalton, Georgia, and provide a link to the Atlantic Coast.

[4] What is now the Southern Terminal and railyard was originally a swamp known as the "Flag Pond," which Knoxvillians considered a health threat and long sought to drain.

On November 8, 1861, Unionist guerillas destroyed five railroad bridges across East Tennessee, forcing Confederate authorities to invoke martial law in the region.

[6] East Tennessee and Georgia president Campbell Wallace, an ardent Confederate, accused the pro-Union Knoxville Whig editor William "Parson" Brownlow of instigating the November 1861 bridge-burning conspiracy, and demanded he be hanged.

[6] After the war, when Brownlow was governor of Tennessee, he seized control of the railroad, claiming Wallace had "basely prostituted" the line to the Confederate cause.

[3] Its tracks stretched as far west as Memphis, as far southwest as Meridian, Mississippi, and Mobile, Alabama, and southeast to Brunswick, Georgia, on the Atlantic Coast.

[3] The Southern immediately began making upgrades to the system's trackage and equipment, and built the Coster Repair Shops, which originally employed over 1,000 workers, and led to the development of the Oakwood neighborhood in North Knoxville.

[12] In 1902, Southern hired architect Frank Pierce Milburn (1868–1926) to design a series of new train stations across the South, including the new terminal in Knoxville.

An obscure Knoxville street musician named Charlie Oaks, who often played at the terminal for "nickels and dimes," wrote a song about the wreck.

[17] The passenger terminal station and express depot, both designed in the same vernacular style with Classical Revival influence, were completed in 1903 and 1907, respectively,[2] and are notable for their signature corbel-stepped gabled roofs.