The river drains a sparsely populated rural agricultural area on the eastern edge of the Great Plains southeast of the Sandhills.

The river is formed in eastern Howard County, approximately 5 miles (8 km) northeast of St. Paul and 20 miles (32 km) north of Grand Island, by the confluence of the North Loup and Middle Loup rivers.

It flows east-northeast, past Fullerton, where it is joined from the north by the Cedar River.

It joins the Platte from the northwest approximately 4 miles (6 km) southeast of Columbus.

A diversion dam southwest of Genoa diverts water to the Loup Canal to hydroelectric facilities in Monroe and then in Columbus.