The river served as an important transportation and trade route for both Native Americans and, from the mid-18th Century on, colonists of European descent who began pushing into the area (predominantly from Virginia, Maryland and the Carolina colonies).

In 1780, during the Revolutionary War, a group of American frontiersmen under George Rogers Clark gathered at the river's mouth for their march up the valley of the Little Miami River, where they conducted operations against British outposts and British-supported Native American tribes, including elements of the Shawnee, Miami, Mingo and Delaware.

The Licking River rises in the Cumberland Plateau of eastern Kentucky, in southeastern Magoffin County (37°31'16"N 82°55'56"W)[5] at the confluence of two smaller streams and an elevation of 1006 feet.

In Rowan County in the Daniel Boone National Forest it is impounded to form the large Cave Run Lake reservoir.

The river basin supports several other fish species, including: redside dace, mimic shiner, streamline chub, slender madtom, blue sucker, paddlefish, and eastern sand darter.

Several state and federal agencies, as well as private organizations such as The Nature Conservancy work to protect the diversity of this important habitat.