The river then runs in Quebec for approximately 15 miles (24 km), re-entering Vermont at Richford and thence to Lake Champlain's Missisquoi Bay.

From its source, the Missisquoi River flows over 117.3 kilometres (72.9 mi), with a drop of 218 metres (715 ft), according to the following segments: Upper course (in Vermont) (segment of 34.7 kilometres (21.6 mi), with a drop of 87 metres (285 ft)) In upper course, Missisquoi River flows north past Troy and North Troy, crosses Big Falls State Park and the village of Lowell.

Intermediate course (in Quebec) (segment of 24.1 kilometres (15.0 mi), with a drop of 10 metres (33 ft)) Lower course (in Vermont) (segment of 58.5 kilometres (36.4 mi), with a drop of 122 metres (400 ft)) It flows west through northern Franklin County approximately 10 miles (16 km) south of the Canada–US border, past the small communities of Richford, East Berkshire, Enosburg Falls, and Sheldon Springs.

On the west side of Interstate 89 in northwestern Franklin County, it turns to the north, passing through Missisquoi National Wildlife Refuge in its lower 5 miles (8.0 km) before entering the south end of Missisquoi Bay, an arm of Lake Champlain that straddles the Canada-Vermont border.

From there, an ancient portage (carrying place) runs 6 miles (9.7 km) to Perkins Landing on Lake Memphremagog.

Abenaki groups met seasonally on the bluffs at Eagle Point in Newport, Vermont, to catch and dry whitefish.

River sections being considered for Wild and Scenic designation are as follows:[citation needed] A Study Committee composed of local appointees[clarification needed] and partner organizations has been evaluating the Wild and Scenic Designation of the upper Missisquoi and Trout rivers.

The group's mission is to facilitate the transfer of information among the ten communities through which the rivers flow - Berkshire, Town of Enosburgh, Village of Enosburg Falls, Jay, Lowell, Montgomery, Village of North Troy, Richford, Westfield, and the Town of Troy, and evaluate the potential benefits of the Wild & Scenic designation.