The largest inland waterway in West Virginia, its watershed has been a significant industrial region of the state since early in the 19th century.

[4]: 13  The river flows generally northwest, in a winding course on the unglaciated Allegheny Plateau, through Fayette, Kanawha, Putnam, and Mason counties, past the cities of Charleston and St. Albans, and numerous smaller communities.

[5] Paleo-Indians, the earliest indigenous peoples, lived in the valley and the heights by 10,000 BC as evidenced by archaeological artifacts such as Clovis points.

Invading from their base in present-day New York, the Iroquois drove out or conquered Fort Ancient culture peoples, as well as such tribes as the Huron and Conoy.

The removal of boulders and snags on the lower river in the 1840s allowed navigation, which was extended upriver by the construction of locks and dams by the U.S. Army Corps of Engineers starting in 1875.

"Ka(ih)nawha" derives from the region's Iroquoian dialects meaning "water way" or "canoe way" implying the metaphor, "transport way", in the local language.

The glottal consonant of the "ih" (stream or river, local Iroquois) dropped out as settlers and homesteaders arrived.

Archaeological artifacts, such as Clovis points and later projectiles, indicate prehistoric indigenous peoples living in the area from the 12,500 BC era.

Those of the Adena culture built at least 50 earthwork mounds and 10 enclosures in the area between Charleston and Dunbar, as identified by an 1882 to 1884 survey by the Bureau of Ethnology (later part of the Smithsonian Institution).

Evidence has been found of the Fort Ancient culture peoples, who had villages that survived to the time of European contact, such as Buffalo and Marmet.

According to French missionary reports, by the late 16th century, several thousand Huron, originally of the Great Lakes region, lived in central West Virginia.

After the Treaty of Fort Stanwix, "The Kanawhas had gone from the upper tributaries of the river which bears their name, to join their kinsmen, the Iroquois in New York; the Shawnee had abandoned the Indian Old Fields of the valley of the South Branch of the Potomac; the Delaware were gone from the Monongahela; the Cherokee who claimed all the region between the Great Kanawha and Big Sandy, had never occupied it."

Under pressure from the Iroquois, most of the Conoy/Kanawha had migrated to present-day Virginia by 1634, where they had settled on the west side of the Chesapeake Bay and below the Potomac River.