It begins as an ephemeral stream on the level surface of the Llano Estacado in Randall County, about 4 mi (6 km) northeast of Canyon, Texas.

It provides the water for Lake Tanglewood and River Falls prior to flowing through the Palo Duro Canyon State Park.

[2] The stream continues in a southeasterly direction through southern Armstrong and northeastern Briscoe County, where it exits Palo Duro Canyon and starts across the rolling red-bed country of central Hall County, where it merges with the Little Red River.

The stream continues across Hall and Childress Counties, merging with Buck Creek and forming the Red River proper, 8 mi (13 km) south-southwest of Hollis, Oklahoma.

[1] When the Prairie Dog Town Fork crosses the 100th meridian at the eastern edge of Childress County, its south bank becomes the state boundary between Texas and Oklahoma.