It drains part of the foothills north of Boulder and the Colorado Piedmont area in the vicinity of Longmont.

Parts of the South St. Vrain Creek form a five-mile (8.0 km) Class 5+ kayak run during normal flows.

East of Lyons, the combined stream flows southeast through farmland and ranch country, passing south of Hygiene and entering Longmont.

East of Longmont it flows generally northeast, meandering through a wide river bottom in ranch country and passing under Interstate 25 south of the intersection with State Highway 66.

It joins the South Platte from the west just upstream from the ruins of Fort St. Vrain and approximately four miles (6.4 km) northwest of Platteville.