Part of US 33 was created in conjunction with the Blue and Gray Trail in 1938 in order to promote a direct and scenic route between the Great Lakes and Virginia's historic Tidewater region.

The road is the main overland link between the Fort Wayne and South Bend metropolitan statistical areas.

Shortly after entering West Virginia and crossing the Ohio River, US 33 turns south, joining I-77 to Ripley.

The route then turns east from I-77, joining US 119 at Spencer, then passing through extremely rural areas of Roane, Calhoun, Gilmer, and Lewis counties.

The four-lane segment continues on through rural areas of Upshur, and Randolph counties, to just a couple miles past Elkins.

Passing through the Monongahela National Forest, US 33 crosses the Eastern Continental Divide between Harman and Onego at about 3,240 feet (990 m) in elevation, entering Pendleton County, then descends the Allegheny Front along Seneca Creek, skirting the north end of Spruce Mountain, at 4,861 feet (1,482 m) the highest point of the Allegheny Mountains.

US 33 then joins WV 28 at Seneca Rocks and continues south in the Potomac River headwaters through scenic forest and farmland landscapes.

Turning eastward from WV 28 at Judy Gap, US 33 crosses North Fork Mountain at about 3,600 feet (1,100 m), with a turnout on the western slope offering a scenic view of the Germany Valley below and the more distant Allegheny Front from Spruce Knob to Dolly Sods.

After Franklin, US 33 continues eastward through rural areas, then climbs steeply to cross Shenandoah Mountain at Dry River Gap at about 3,450 feet (1,050 m) into Rockingham County, Virginia.

These include Ohio segments from St. Marys to Wapakoneta; Huntsville (near Bellefontaine) to Dublin (a northwestern suburb of Columbus); and bypasses around Lancaster, Nelsonville,[8][9] Athens, and Pomeroy.

In West Virginia, US 33 from Interstate 79 near Weston east nearly to Elkins is four-lane, built as part of Corridor H of the Appalachian Development Highway System.

The route's steep grade up Shenandoah Mountain in easternmost West Virginia has been widened, with some sharp curves improved.