The watershed encompasses approximately 4,100 square miles (11,000 km2) of highly diverse habitats, including alpine canyons, forest, rangeland, agricultural lands, and urban areas.

It flows west-southwest near the town of Atlanta, joining the North Fork to form the Boise River, approximately 15 miles (24 km) southeast of Idaho City.

It flows generally southwest, descending through a basalt canyon to fill the Anderson Ranch Reservoir, then turns northwest in central Elmore County.

Downstream from its confluence with the South Fork, the river flows generally west, adds the major tributary of Mores Creek along Highway 21, and passes through Lucky Peak Dam to emerge from the foothills southeast of Boise.

At an approximate elevation of 2,100 feet (640 m), it enters the Snake River, the Idaho-Oregon border, west of Parma and three miles (5 km) south of Nyssa, Oregon.

[citation needed] On the lower (warmwater) course of the river, low summer flows and poorer water quality from agricultural runoff limit fishery production.

This is especially true immediately downstream from the outflow of Anderson Ranch reservoir, where the South Fork takes on the characteristics of a classic "tailwater" for over 5 miles (8 km) from the put-in below the dam to Cow Creek Bridge.