It is a tributary of the Connecticut River, which flows to Long Island Sound.

Counting the lake would add 2.7 miles (4.3 km) to the river's length.

The Mascoma River begins at Cummins Pond in a heavily forested part of the town of Dorchester and flows south into the town of Canaan, collecting water flowing from Reservoir Pond, Clark Pond, and Canaan Street Lake before reaching the Indian River.

Here it turns west, collecting tributaries arriving from Goose Pond and Crystal Lake, before it passes through the mill town of Enfield and arrives at Mascoma Lake.

For most of its path from the Indian River to the Connecticut, the Mascoma River and its valley have influenced the location of numerous transportation routes, including U.S. Route 4 and an inactive, state-owned rail line known as the Northern Railroad, most of which has now been converted to a rail trail.