The Prairie Dog Town Fork, the main tributary of the Red River, rises at the junction of Palo Duro and Tierra Blanca creeks in central Randall County, northeast of Canyon (at 35°00' N, 101°56' W). It flows 160 miles southeastward through the Palo Duro Canyon, across southwestern Armstrong and northeastern Briscoe counties, and out of the canyon and eastward across the broken country of central Hall and Childress counties, to its confluence with the North Fork of the Red River, twelve miles northeast of Vernon (at 34°24' N, 99°32' W); there the Red River proper begins. When the Prairie Dog Town Fork crosses the 100th meridian at the eastern line of Childress County, its south bank becomes the state boundary between Texas and Oklahoma and the northern county line of Hardeman and Wilbarger counties.
Spaniards were the first White men to see the Prairie Dog Town Fork; in the 1780s Pedro Vial and Santiago Fernández followed it during their trading expeditions between Santa Fe and the Taovaya villages on the Red River. Randolph B. Marcy and George B. McClellan first determined it to be the main fork of the Red River after exploring it in the summer of 1852; this designation later influenced the United States Supreme Court decision to award the disputed Greer County to Oklahoma in 1896. The road in Palo Duro Canyon State Scenic Park crosses the stream five times, and campgrounds are available on the creek. Lake Tanglewood was formed in the early 1960s by a dam on the Prairie Dog Town Fork in northeastern Randall County.