It drains a remote area of the Cascade Range east of Sweet Home in the watershed of the Willamette River.

It rises in the Cascades in eastern Linn County in the Willamette National Forest, about half a mile west of Iron Mountain.

It flows briefly north, then generally west and southwest through the mountains and Middle Santiam Wilderness.

Approximately 4 miles (6 km) downstream from the dam it joins the South Santiam from the northeast as an arm of Foster Reservoir.

Named tributaries of the Middle Santiam River from source to mouth are Cougar, Holman, Lake, South Pyramid, Bachelor, Pyramid, Donaca, Jude, and Egg creeks, followed by Fitt, Chimney, Sixes, Bear, and Twin Falls creeks.