Composed of Mischta- and -assini, meaning “large stone” in the Cree language, the name Mistassini is explained by the presence of a large rock once regarded as sacred by the Cree people, which Father Laure located in the Mistassini River. This rock, associated with the spirit Tchigog8che8, guardian of fair and foul weather, was said to be a place of spiritual practice where tobacco, incense, and the remains of beavers and fish were left as offerings. To this day, the stone remains undiscovered.
The presence of Indigenous Peoples along the Mistassini River is believed to date back to around the year 1000, according to archaeologists who have studied the site. The First Nations of that period followed a nomadic way of life and frequented the river primarily for fishing, including walleye, ouananiche (landlocked salmon), yellow perch, and northern pike. In the late 19th century, Father Crépeau, a monk from the Trappist community of Mistassini, still noted the presence of seasonal Indigenous camps where fish were caught and dried, specifying that these stays generally lasted between five and fifteen days.
Stretching nearly 300 kilometres in length and encompassing a drainage basin of approximately 21,000 square kilometres, the Mistassini River represents the second-largest watershed in the region. Beyond the first waterfall, shallow waters restricted travel to canoes, requiring a series of portages. Initially an important communication route between northern and southern territories, the river later became a key corridor for the fur trade before gradually being incorporated into the process of settlement and colonization.