Chartered on January 24, 1848, in Greeneville, Tenn., the East Tennessee and Virginia Railroad was formed for the purpose of establishing a rail communication between Knoxville and the State of Virginia. Stock subscription books were made available in 17 East Tennessee towns, however, the majority were sold in the Jonesborough region in Washington County. After the initial sale of stock, a committee of twelve (eight of whom were from Jonesborough) was elected to lead the company. Leading the committee was Samuel B. Cunningham, a surgeon and community leader in Jonesborough, who was named president.

Completion of the railroad came in 1858 at a total reported cost of $2.5 million. Dr. Cunningham served as president throughout the construction, resigning his post in 1859. During the Civil War, the East Tennessee and Virginia Railroad became the object of much destruction by soldiers and Unionist civilians alike, as it was a vital link in the connection between Atlanta and Richmond. In 1869, a merger with the East Tennessee and Georgia Railroad formed the East Tennessee, Virginia, and Georgia Railroad, operating from Chattanooga to Bristol.