An important commercial route in the 19th century, it flows generally southward through the eastern hill country of Ohio.

Noted frontier explorer Christopher Gist reached the Big Sandy Creek tributary of the river on December 4, 1751.

Traveling downriver, he recorded arriving on December 14 at the western Wyandot town of Muskingum, at present-day Coshocton.

Zanesville was settled by European Americans in 1799 at the site where Zane's Trace crossed the Muskingum at the mouth of the Licking River.

In the mid-19th century the Muskingum was an important commercial shipping route, with dams and locks controlling the water level to allow boats to travel up and down the river.