[4] The Moisie flows south from Lake Opocopa near the Labrador border to the north shore of the Saint Lawrence River east of Sept-Îles, Quebec.

Another popular theory is that it come from the Old French word moise or moyse, meaning "wet river bank.

However, in 2003, the Quebec government protected a large part of the river's watershed as an aquatic reserve and has prevented activities such as logging, mining, and power projects, but has permitted traditional uses such as hunting and fly-fishing.

[2][5] The Quebec North Shore & Labrador Railway follows the lower section of the Moisie River and provides access to the Quebec-Labrador plateau from which canoeists can reach its headwaters.

The river's remoteness makes it have very few access points, and if an accident occurs involving a canoeist, the most common form of evacuation is by seaplane.

A forest fire in the summer of 2014 destroyed a lot of the ecosystem surrounding the river and made it unsafe for campers and canoeists to explore and venture.