The highway connects the independent city of Harrisonburg (which also serves as the seat of Rockingham County), the town of Elkton, and an entrance to Shenandoah National Park.

SR 33 continues from US 33's eastern terminus as a state-numbered extension of the U.S. Highway that connects Richmond with Virginia's Middle Peninsula.

East of Rawley Springs, the highway veers away from the river, leaves the national forest, and passes through a low, wide gap in Great North Mountain to enter the Shenandoah Valley.

After I-81, US 33 expands to six lanes, passing through a commercial area that includes the Harrisonburg Crossing shopping center and the Valley Mall.

Eastward, the route returns to a four-lane highway, and is named Spotswood Trail at the city limits of Harrisonburg.

After cresting the Blue Ridge, US 33 enters Greene County and has a more gentle descent of the eastern side of the mountain, where the highway follows Swift Run to the hamlet of Lydia, then passes around the north side of Powell Mountain and meets the stream again west of Stanardsville, where the road expands to a four-lane divided highway.

The two highways pass the Exchange Hotel at their underpass of the Washington Subdivision, the Charlottesville–Orange rail line owned by the Buckingham Branch Railroad.

Continuing eastward across the Piedmont, US 33 heads southeast into Hanover County, where the highway is named Mountain Road.

The route then passes through the village of Montpelier, after which it meets the western end of SR 54 (Patrick Henry Road).

In Dumbarton, US 33 meets the western end of SR 356 (Hilliard Road) and has a partial cloverleaf interchange with I-64 with a flyover ramp from westbound I-64 to eastbound US 33.

[1][2] US 33 enters Richmond, an independent city, just before the highway meets US 250 (Broad Street) near The Shops at Willow Lawn.

US 33 and US 250 intersect SR 161 (Arthur Ashe Boulevard) northwest of the Science Museum of Virginia, in the former Broad Street railroad station.

At the east edge of town, the business route meets the southern end of SR 230 (Madison Road).