The Guyandotte River is formed in southwestern Raleigh County by the confluence of three streams, Winding Gulf, Stonecoal Creek, and the Devils Fork.

[2] The Guyandotte flows initially west northwest into Wyoming and Mingo counties.

It enters the Ohio River from the south at Huntington, about 5 mi (8 km) east of the city's downtown.

In Mullens, an active watershed organization is working to reduce pollution in the headwaters of the Guyandotte River.

UGWA has garnered much public support and produced results in partnering with numerous local, state, and federal agencies.