The warm water in the river attracts large numbers of manatees, and Kings Bay, at the head of the river and the location of 28 of the springs, harbors approximately 350 manatees during the winter. Some biologists consider Crystal River to be the most important refuge for manatees in the United States.
In the first half of the 19th century Crystal River was known as Weewahiiaca, believed to be from the Creek language words wewa, meaning "water", and haiyayaka, meaning "clear". The city of Crystal River is located on the river. The Crystal River Energy Complex, which consists of four coal-burning power plants and the Crystal River 3 Nuclear Generating Station, is located near the mouth of the river. The Crystal River Archaeological State Park is located on the river.