The river's name may originate from a French word moisie meaning "rotten" . But this is not certain and other hypotheses exist.
The Mishta-shipiunnu („Innu from the Moisie River“) call it Mishta-shipu ("Great River"; mishau - ″big, great″ and shipu - ″river“). As they have done for thousands of years, they continue to use the river to reach their northern hunting and fishing grounds. Large parts of the river were also protected by private fishing clubs. There were recent attempts to develop hydroelectric projects on the Moisie. However, in 2003, the Quebec government protected a large part of the river's watershed as an aquatic reserve. This prevents activities such as logging, mining and power projects, but permits traditional uses such as hunting and fly-fishing.
The Moisie River is popular with experienced canoeists concerning its whitewater. It flows through a deep valley of glacial origin. The width of the valley varies considerably. The views of mountains and cliffs cause it to be used for canoe camping. 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.