The river rises near Francs Peak in the Absaroka Mountains in the southwest corner of the Big Horn Basin. It joins with the Wood River and leaves the mountains near the town of Meeteetse, continuing through the southern parts of Park County and Big Horn County before flowing into the Big Horn River near Greybull. Much of the upper river is considered a top trout stream, hosting the best genetically pure populations of Yellowstone cutthroat trout in the region. In 1981, a colony of black-footed ferrets was discovered on the Pitchfork Ranch near Meeteetse. The animal had previously been thought to be extinct.