The highway runs 21.439 miles (34.503 km) from VT 11 in Londonderry east to U.S. Route 5 (US 5) in the incorporated village of Bellows Falls in the town of Rockingham.

The highway heads south and follows the Middle Branch Williams River into its headwaters in the town of Windham.

VT 121 curves east and enters the valley of the Saxtons River at the hamlet of Lawrence Four Corners.

West of Hinkley Brook, VT 121 becomes paved again, and the highway veers onto Main Street in the Grafton Village Historic District.

The highway follows Old Terrace through the Bellows Falls Neighborhood Historic District to its eastern terminus at a four-legged intersection with US 5.