The river issues from Lake Hicpochee, in southeastern Glades County, approximately 10 mi (16 km) west of Clewiston.
It enters the Gulf of Mexico 10 mi (16 km) southwest of Fort Myers in San Carlos Bay, protected by Sanibel Island.
His company removed the rock ledge that formed the falls and rapids below Lake Flirt and straightened the upper reaches of the Caloosahatchee River.
Recent programs by the state government have attempted to establish minimum flow levels in the river, in part to help restore the water supply to the Everglades.
A federal wildlife refuge for manatees has been established at the mouth of the river on San Carlos Bay near Fort Myers.