It goes through the cities and towns of Norfolk, Portsmouth, Suffolk, Petersburg, Farmville, Lynchburg, Roanoke, Christiansburg, Blacksburg, Tazewell, and Grundy, in Virginia; Princeton and Bluefield in West Virginia; and Pikeville, Georgetown, and Frankfort in Kentucky.

The section from Interstate 81 at Christiansburg, Virginia, to U.S. Route 23 in Pikeville, Kentucky, is Corridor Q in the Appalachian Development Highway System.

It is a major thoroughfare through southern Hampton Roads and connects the area to Petersburg.

The earliest origins of this road were as part of the track once known as the Trader's Path, a Virginia colonial trail dating from the 17th century that led from Augusta County to present-day Roanoke.

[2] In the pre-Interstate era, US 460 was a major highway, passing from Frankfort through Louisville, Kentucky and Evansville, Indiana, and ending in St. Louis, Missouri, after crossing the MacArthur Bridge.

However, its parent route, US 60 has not been supplanted by I-64 and converted to a state highway in the greater Louisville area.

When Fishtrap Lake was created in Pike County, Kentucky, US 460 was realigned to its current route from Salyersville to Paintsville.

The current alignment is a rural two-lane road winding along the rivers and mountains of Virginia and Kentucky.