It drains an arid volcanic plateau region east of the Cascade Range in the watershed of the Klamath River.

It is formed by the confluence of its north and south forks in eastern Klamath County, approximately 35 miles (56 km) east-northeast of Klamath Falls at 42°26′16″N 121°06′34″W / 42.437650°N 121.109435°W / 42.437650; -121.109435 (Sprague River source).

The North Fork Sprague River, 30 miles (48 km), rises in southwestern Lake County in the Fremont National Forest near Gearhart Mountain at 42°31′44″N 120°49′06″W / 42.5287618°N 120.8183115°W / 42.5287618; -120.8183115 (North Fork Sprague River source) and flows southwest.

The South Fork Sprague River, 30 miles (48 km), rises northeast of Quartz Mountain Pass at 42°28′54″N 120°47′13″W / 42.4815400°N 120.7869201°W / 42.4815400; -120.7869201 (South Fork Sprague River source) and flows west-northwest.

It joins the Williamson from the east at Chiloquin, about 10 miles (16 km) north of the mouth of the Williamson on Upper Klamath Lake at 42°34′16″N 121°52′28″W / 42.5712475°N 121.8744593°W / 42.5712475; -121.8744593 (Sprague River mouth).