The historic James River & Kanawha Turnpike, now the route of U.S. 60 and parts of Interstate 64, began as a meandering game trail. Native Americans used the trail for centuries to reach the Kanawha salt licks, and later it was an important passage for European immigration through the Appalachians. Col. Andrew Lewis's army traveled over it to the Battle of Point Pleasant in 1774. By 1785, the state of Virginia authorized construction of the Old State Road, along the path of the Lewis trail. In 1791, the road was improved to the head of navigable water on the Kanawha River at Kellys Creek (present Cedar Grove), where westward travelers secured bateaux or flatboats made at "the Boatyards" for their downstream journey.

Opened to the Ohio River by 1800, the Old State Road underwent major repairs in 1803 and received legislative authorization to collect tolls for maintenance in 1809. However, the growing importance of Kanawha salt necessitated a more reliable all-weather road. Pursuant to an 1820 legislative act, Virginia authorized the James River Company "to make a convenient road by the most practicable route from the James to the Great Falls of the Kanawha," near present Gauley Bridge, as an overland connector in the company's James River & Kanawha Canal project. Company surveyors located the road through Greenbrier and Fayette counties on the north side of the New and Kanawha rivers because it required fewer bridges and furnished better grades at lower cost. Covered bridges over the Greenbrier and Gauley rivers opened in 1822, and by 1824 the road ran from Lewisburg to Montgomery's Ferry, 25 miles above Charleston.

In 1829, the Virginia legislature authorized extending the road to the mouth of the Big Sandy River on the Ohio. Completed in 1832, this road crossed the Kanawha at Charleston, followed an existing route along the south side of the river to Coalsmouth (present St. Albans), then followed Teays Valley to the Mud River. It crossed the Guyandotte River at Barboursville and terminated at present Kenova on the Ohio. A branch road extended to the town of Guyandotte. Following the so-called "central line," this turnpike was a significant east-west passage until the Civil War.

Completion of the Chesapeake & Ohio Railroad to Huntington in 1873 ushered in a period of decline for the turnpike that lasted until the automobile era. By World War I, the Kanawha route experienced a rebirth as part of the Midland Trail, a transcontinental highway that in 1926 became U.S. 60. It remained the primary east-west route through southern West Virginia until the completion of Interstate 64 in 1988, when it became a secondary route for local traffic. In response, business owners and elected officials in Greenbrier, Fayette, and Kanawha counties formed the Midland Trail Scenic Highway Association to promote scenic, historic, and recreational opportunities along the old route. In 1989, Governor Arch Moore designated U.S. 60 from White Sulphur Springs to Charleston as the Midland Trail Scenic Byway. This original 119-mile segment became a National Scenic Byway in 2000, and in 2001 the remaining West Virginia portion of U.S. 60 from Charleston to Kenova became a State Scenic Byway.