Near the town of Cherry Creek, it is joined by Cherry Creek and flows into Missouri at Lake Oahe, approximately 32 mi (50 km) NNW of Pierre, South Dakota, with the lower 35 mi (56 km) of the river forming an arm of Lake Oahe.

Because of the proximity to the Black Hills and its mining industry, the Cheyenne historically picked up large quantities of zinc, arsenic, and cyanide.

[10] Sedimentation is a major water quality concern for the Cheyenne watershed, potentially resulting in reduced storage capacity for reservoirs.

Major water issues in the Cheyenne, reflect those of the larger Missouri River basin and stem from anticipated effects from a warming climate.

[11] Demand for water from agriculture for irrigation, greater threats to viable habitat for endangered species and wildlife are large concerns directly related to increasing temperatures and evapotranspiration.