The Chesapeake & Ohio was a major force in opening the coalfields of southern West Virginia in the years after the Civil War. The railroad provided the impetus for the growth of Huntington in the west, White Sulphur Springs in the east, and towns in between such as Hinton and Thurmond. Many West Virginians can name members of their families who were, or still are, employees of the C&O and its successors.

The Chesapeake & Ohio Railroad was created in 1868 by the merger of the Virginia Central Railroad and the Covington & Ohio Railroad. At the beginning of the Civil War, the Virginia Central extended from Richmond to Waynesboro and was the second largest railroad in the state. While the Covington & Ohio had been chartered in 1853 to build from the western terminus of the Virginia Central to the Ohio River, no construction had taken place at the outbreak of the Civil War. The Virginia Central, located where the fighting raged, suffered significant damage during the war. When the war ended, Gen. William C. Wickham, a Confederate cavalry officer, became president of the railroad and restored the entire line to operation early in 1866.

In July 1867, the Virginia Central reached Covington, near the boundary between Virginia and the new state of West Virginia. Wickham also became president of the Chesapeake & Ohio after the 1868 merger and immediately began seeking funds to extend the railroad to the Ohio River.

The C&O soon attracted the support of Collis P. Huntington, one of the greatest railroad entrepreneurs in American history. Huntington had recently been the major figure in the completion of the first transcontinental railroad, the Union Pacific-Central Pacific. He saw the C&O as the eastern section of a true transcontinental railroad. His contacts with New York financiers were desperately needed by the C&O. To benefit from these contacts, however, the board and the stockholders of the railroad were forced to reorganize the company, turning operations over to Huntington and his friends.

Once in control, Huntington expanded the railroad rapidly. Construction started west from Covington and east from the newly developed town of Huntington on the banks of the Ohio. Using more than 7,000 men (including the legendary John Henry, the "steel driving man"), and well over the projected construction cost of $15 million, the line was completed on January 29, 1873. Construction was expensive and difficult because of the mountains between Covington and Hinton. West of Hinton the line followed the New River for a considerable distance, the narrow valley also a challenge to construction workers. Many fatalities and injuries resulted.

The difficult construction and the rapid expansion of the C&O, in addition to the national depression of 1873, forced the company into default. In 1878, the Chesapeake & Ohio Railroad was sold at foreclosure, reorganized, and renamed the Chesapeake & Ohio Railway. Financial conditions gradually improved as coal mines were opened along the route. A major step forward took place in 1882 when a 75-mile line was constructed from Richmond to Tidewater at Newport News, connecting the railroad with ocean shipping.

In the 1880s, the C&O pushed west to Cincinnati and smaller railroads were absorbed at a rate too rapid to sustain. Consequently, the line was forced into receivership again in 1887. A foreclosure sale was averted when J. P. Morgan interests purchased control of the company and instituted a successful financial recovery. In the process Huntington's role with the C&O ended, and his place was taken by Melville E. Ingalls.

The Ingalls era (1888—1900) began with the entry of the C&O into Cincinnati. Ingalls's leadership provided stability and with financial support from Morgan the company continued to expand. By 1900, the C&O had more than doubled the mileage it operated, new locomotives and rolling stock had been purchased, the line had been ballasted and re-laid with heavier rails, and the company paid a dollar per share annual dividend.

In the first decade of the new century, the Pennsylvania Railroad and the New York Central purchased large amounts of C&O stock in an effort to control rates for shipping coal. To further this end, the C&O purchased some of the small coal-hauling railroads in West Virginia that connected with the C&O, such as the Coal River & Western Railroad and the Guyandot Valley Railroad. Branches to Big Creek, Buffalo Creek, Rum Creek, Piney Creek, Cabin Creek, and Dingess Run, for example, were also constructed. The 98-mile Greenbrier Railway Company, purchased by the C&O in 1907, ran up the Greenbrier Valley to Bartow. Completed in 1904, it was built to provide access to timber for the large sawmills at Ronceverte. Eventually known as the Durbin Branch, it connected with what is now the Cass Scenic Railroad at Cass.

In Ohio the C&O gradually absorbed the Hocking Valley Railroad after 1905, giving connections to Columbus and Toledo. Other expansion in the Midwest gave the C&O access to Chicago and the Great Lakes. After World War I, the C&O went through several leadership changes before ending up under the direction of brothers Oris P. and Mantis J. Van Sweringen, colorful real estate developers in Cleveland. The Van Sweringens attempted to combine their railroads—the C&O, the Erie, the Pere Marquette, and the Nickel Plate—into one major system. While the Interstate Commerce Commission refused to allow the merger and the Van Sweringen empire was eventually disbanded, one result was the C&O's acquisition of the Pere Marquette Railroad, operating primarily in Michigan.

Because of its coal traffic the C&O survived the Great Depression better than most railroads. From 1937 to 1954, under the direction of Robert R. Young, the railroad grew to a 5,100-mile system with 35,000 employees and an annual revenue of $319 million. In 1962, with Walter J. Tuohy as president, the C&O acquired the faltering Baltimore & Ohio, in a contest with the New York Central which had earlier wanted to merge with the C&O. In 1972, the C&O, B&O, and Western Maryland were merged into the Chessie System. In 1980, the current CSX corporation was created, merging the Chessie System and the Seaboard Coast Line. Today, as one of the major rail systems in the United States, CSX has acquired significant parts of Conrail, thus reducing the major railroad systems of West Virginia to two: CSX and Norfolk Southern.