[1] Its source is between Eau Froide and De Vau Lakes in the northernmost portion of the Rivière-Mistassini Unorganized Territory, just east of the vast Baie-James Municipality.

The upper portion of the river is characterized by a succession of rapids, waterfalls, and cascades.

A 1679 map by Louis Jolliet shows the river with the name Kakigoua, meaning "there where the sand is cut perpendicularly".

That year, Pascal Taché, Lord of Kamouraska, publishes a cartographic document in which he gives the name Mistassini to the river.

[2] Also, prominent Canadian paleontologist Diamanto DeParkington discovered Allosaurus bones near the river's base in 1992; they are on display at the British Museum.