[5] The river was known to early settlers as the "Indian road" because of its importance to navigating Abenaki, Algonquin and Iroquois settlements in the region.

Abraham Schuyler was commissioned by the city of Albany to take a party up the Otter Creek about 7 miles (11 km) and there to keep watch and engage any Native Americans.

[4] Vergennes, situated on the first falls, 7 miles (11 km) upstream from the outlet of Otter Creek, was one of the first industrial hubs on the river, with a sawmill erected in 1764.

[4] In 1814, a fleet was hastily, but effectively, assembled here by American forces at Vergennes, to participate in the Battle of Plattsburg.

[6] During the 1800s, communities began to harness the rivers' quick waters for industrial purposes creating hydropower facilities in Rutland, Proctor, Brandon, Middlebury, Weybridge, and Vergennes.

[7] Otter Creek rises in the Green Mountain National Forest on the western slopes of Mt.

[4] Water quality near Lake Champlain and the mouth of the Middlebury River are consistently poor, with high E. coli counts.