Running parallel to and west of Interstate 81, SR 42 consists of three sections, with gaps filled by secondary routes in between.

Another major piece, from near Clifton Forge to Buffalo Gap, parallels the old Virginia Central Railroad.

SR 42 continues past Groseclose Store and Ceres, meeting State Route 623 at Sharon Springs, the source of the North Fork Holston River.

SR 42 continues to follow Walker Creek through Giles County, passing White Gate before ending at State Route 100 at Poplar Hill.

It crosses old US 460 in Newport and begins following Sinking Creek in a general east-northeasterly direction.

SR 42 continues near the Cowpasture River past Nimrod Hall to State Route 39 at Millboro Springs.

Once SR 42 passes through Buffalo Gap, the land is flatter, and the road heads cross-country, still in a north-northeasterly direction, past Churchville (where it crosses U.S. Route 250), Stover, Parnassus, Moscow, Mount Solon, and Mossy Creek.

SR 42 continues in its north-northeasterly direction from Harrisonburg, passing Edom, Broadway (where it crosses State Route 259), and Timberville (where it weets the west end of State Route 211 and crosses the North Fork Shenandoah River, which also passes through Broadway).

It begins westbound at the northern terminus of the SR 42/257 overlap, and turns north onto Main Street less than a block later.

The route continues to run along the northwest side of SR 42 until it finally terminates at a poultry farm just north of town.