The eastern segment of US 2 begins in New York at an intersection with US 11 just one mile (1.6 km) south of the Canadian border in Rouses Point.

From there, it travels south to Burlington, where it begins to closely parallel I-89 and the Winooski River all the way to Montpelier and Washington County.

An improved road between the main settlements of Burlington and Montpelier was first established from old footpaths in 1805, when the 36-mile (58 km) Winooski Turnpike was chartered by the state of Vermont.

The old turnpike road utilized the relatively flat banks of the Winooski River to connect the two major towns and opened to traffic several years after the company was chartered.

From St. Johnsbury, the Roosevelt Highway turned southeast toward Portland along modern VT 18 while US 2 continued east along former Route 15 to Bangor.

[12] When US 2 was assigned, it was overlaid on the preexisting VT F-1, following the route and the ferry to the New York state line, where US 2 initially ended.

[2] Much of the portion of VT 2A that runs through Williston has been expanded from two to four lanes, particularly the stretch between US 2 and I-89, to accommodate the many restaurants, offices, and stores that have been developed there.

The rest of the road runs through rural Caledonia County and crosses a bridge over I-91 with no access, just south of exit 21 before finally terminating at US 2 in St. Johnsbury.