In Vermont, the road runs south–north from the Massachusetts state line near Guilford to the international border.

The highway serves the major towns of Brattleboro, Hartford, and St. Johnsbury, along with the city of Newport near the Canadian border.

US 5 enters the southern end of Vermont in Windham County at the Massachusetts–Vermont state line just north of Bernardston and just south of Guilford.

[5] North of Brattleboro, after VT 9 turns east, US 5 crosses back over the Interstate to the west side.

[6][7] North of Putney, it crosses over I-91 to serve the towns of Westminster, Bellows Falls, and Rockingham.

[13][14] Now on the east side of I-91, US 5 winds around the northwest edge of White River Junction, where it hooks up with US 4.

US 4 and US 5 run concurrent for half a mile (0.80 km) as a divided four-lane surface arterial, crossing the White River.

US 5 continues north along the Passumpsic River from St. Johnsbury for about 7.5 miles (12.1 km) until it reaches the town of Lyndon.

US 5 passes through West Burke, Willoughby State Forest, and Barton before reaching the town of Orleans, 25 miles (40 km) north of Lyndon.

In the town of Orleans, US 5 crosses to the west side of the Interstate, concurrent with VT 58 for half a mile (0.80 km).

[24] In Newport, US 5 picks up a five-mile-long (8.0 km) concurrency with VT 105 that takes US 5 across I-91 and into the village of Derby Center.

In 1922, before the United States Numbered Highway System's creation, US 5 traversed through Vermont as Route 2, the Connecticut River Way.