There are four hydroelectric generating stations on this last section of the river (operated by Brookfield Power Inc.), and at its mouth is the Michipicoten Provincial Park that was the site of a trading post.

The French explorer and cartographer Samuel de Champlain included the Michipicoten River in a map of North America as early as 1632.

A French fur trading post was built at the river's mouth in the early 18th century, at a site sometimes called "Fort Michipicoten".

It was eventually reopened later in the 18th century under the British, and the Hudson's Bay Company and North West Company both opened competing trading posts at the river mouth, with the former building trading posts along the river's route in the 1770s.

In 1781, Philip Turnor, the HBC's first full-time surveyor, performed a detailed survey of the river, followed by many upgrades to the portages.

[4]: 18  Settlements around the river, such as Wawa, became boom towns due to a short-lived gold rush in the area around the turn of the 20th century.