[5] In Quebec, the river forms the boundary between the Minganie and Golfe-du-Saint-Laurent Regional County Municipalities before draining into the Gulf of Saint Lawrence, about 370 kilometers (230 mi) east from Sept-Îles.

The name is of Innu origin, who call it Nutahquaniu Hipu, meaning "river where black bear is hunted".

[6] The last 18 kilometers (11 mi) of the river forms a large sandy estuary, separated from the gulf by Natashquan Point and Cape Tiennot.

[6] In 1534, Jacques Cartier sailed by the area and named Cape Thiennot after a ship captain that had settled at that location.

[3] From as early as 1710, a trading post was established on the left (south) bank of the Natashquan River and later on the opposite bank (at the river's mouth at present-day Natashquan FN Reserve) to conduct fur trade with the indigenous Innu people.

The post was acquired by the Hudson's Bay Company in the middle of the 19th century, but abandoned circa 1914 due to lack of profitability.

In view of the rapidly declining Atlantic salmon population catch-and-release should have been implemented on all rivers apart from northern Quebec.