Indiana

From its terminus at US 20 on the southeast side of Elkhart, US 33 is a winding road that cuts diagonally from northwest to southeast through Northeast Indiana and serves as Main Street or a portion of Main Street in several cities and towns, including Elkhart, Dunlap, and Churubusco. The road is the main overland link between the Fort Wayne and South Bend metropolitan statistical areas.

On the west side of Fort Wayne, US 33 joins US 30 near Interstate 69 (I-69), then follows the Interstate south, intersecting with State Road 14 (SR 14) and US 24 before turning east to follow the I-469 bypass around the southwest side of Fort Wayne. At the intersection with SR 1 south of the Fort Wayne International Airport, I-469/US 33 turns to the northeast until it intersects US 27 at the Fort Wayne suburb of Hessen Cassel, where US 33 splits off to the southeast to follow US 27 as a combined highway toward Decatur.

At Decatur, US 33/US 27 becomes a north–south road before it intersects with US 224 and continues as such until US 33 splits from US 27 south of Decatur and heads east toward the Ohio state line, intersecting SR 101 at Pleasant Mills along the way.

Ohio

In Ohio, the highway runs at a generally southeast–northwest angle from the west-central to the southeastern part of the state, passing through mostly rural territory except for a significant portion running through downtown Columbus. Most of the route in the state, particularly east of Columbus, is expressway. The highway crosses over the Ravenswood Bridge into West Virginia.

West Virginia

View west along US 33 in Pendleton County, West Virginia

US 33 extends 248 miles (399 km) in West Virginia, from the Ohio River at Ravenswood to the Virginia state line atop Shenandoah Mountain west of Harrisonburg, Virginia.

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.

US 33 intersects I-79 at Weston. From I-79 east, US 33 is a four-lane highway, part of Corridor H of the Appalachian Development Highway System. The four-lane segment continues on through rural areas of Upshur, and Randolph counties, to just a couple miles past Elkins.

At Harding, US 250 joins US 33 for several miles after Elkins, where US 33 joins West Virginia Route 55 (WV 55) and returns to a two-lane road, except for a seven-mile (11 km) section of four-lane across Kelly Mountain between Canfield and Bowden. 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. US 220 joins US 33 for about half a mile in Franklin. 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.

Virginia

View east along US 33 just after entering Virginia from West Virginia in Rockingham County

US 33 extends 139 miles (224 km) in Virginia from the West Virginia state line west of Harrisonburg across the Shenandoah Valley, Blue Ridge Mountains, and Atlantic Piedmont to Richmond. It enters Virginia from West Virginia on Shenandoah Mountain. After going down the mountain, it passes through the unincorporated community of Rawley Springs. After traveling nine miles (14 km) from Rawley Springs, reaches the independent city of Harrisonburg and intersects major routes State Route 42 (SR 42), US 11, and I-81 before leaving the city. The four-lane highway passes around the southernmost end of Massanutten Mountain, towards Elkton. There, it intersects US 340. After leaving Elkton, the highway heads towards the Blue Ridge Mountains, once it gets to the mountains, it reduces to two lanes and becomes three lanes a few times. At Swift Run Gap it intersects Skyline Drive and enters Greene County. After going down the mountains, it goes back to four lanes and heads south of Stanardsville. After that, the route heads southeast towards US 29 in Ruckersville. After that, it heads south east and enters Orange County. It heads east north of the Albemarle County line and intersects SR 20 on a concurrency. After that, it goes through a small part of the Southwest Mountains towards Gordonsville. It goes on a roundabout with US 15 and SR 231. US 33 heads east with US 15 and into Louisa County. Shortly after, US 33 splits from US 15 and heads southeast towards Louisa. In Trevilians, it intersects SR 22.The route then goes east toward Montpelier. In Montpelier, the route goes southeast towards Interstate 295. After I-295, US 33 goes a few miles to an interchange with I-64. Just after, the route meets US 250. The two routes head southeast into Downtown Richmond. Both meet their eastern terminus there. From Richmond, "Route 33" continues east as SR 33 across the Atlantic coastal plain through the Tidewater region of the Middle Peninsula to reach the Chesapeake Bay at Stingray Point just east of Deltaville.