It rises in the high Cascades north of Fish Mountain, formed by the confluence of two short forks in eastern Douglas County approximately 20 miles (32 km) northwest of Crater Lake.

It flows generally southwest through a remote canyon in the Umpqua National Forest to Tiller, then west past Milo and Days Creek.

It emerges into the South Umpqua Valley at Canyonville, passing under Interstate 5 and flowing north along the highway past Tri-City, Myrtle Creek, and Roseburg.

Using the land claims settlement of $1.5 million, the Cow Creek Band operates a casino, hotel, convention center, and other businesses in Canyonville on the South Umpqua River.

South Umpqua Falls near Tiller is the site of a popular picnic area and United States Forest Service campground near the river.