The river rises southwest of Hartville in northern Stark County, and initially flows westward, through Uniontown into southern Summit County, where it passes through the Portage Lakes area south of Akron, and Barberton.

South of New Philadelphia, the river turns southwest and west, flowing past Tuscarawas, Gnadenhutten, Port Washington, and Newcomerstown, sites of former Lenape people villages at the time of the American Revolutionary War, into Coshocton County, where it joins the Walhonding River at the city of Coshocton (a former major Lenape site) to form the Muskingum River.

[4] From Barberton downstream, the Ohio and Erie Canal was constructed parallel to the river in 1828–30 to provide for improved transportation of products and passengers.

[1] As of 2006[update], the state of Ohio Environmental Protection Agency has recommended limits on the consumption of fish taken from the river, due to contamination by mercury and PCBs.

[4] At the United States Geological Survey's stream gauge in Newcomerstown, the annual mean flow of the river between 1922 and 2005 was 2,591 ft³/s (73 m³/s).