Guyandotte was founded in 1799 by settlers including descendants of French families - LeTulle, Holderby, Buffington - whose names still appear on the gravestones of the eighteenth-century cemetery in the neighborhood. The land was part of the Savage Grant, a 28,628-acre parcel in western Virginia given to veterans of the French and Indian War who had served under Captain John Savage. Nearly all of present-day Huntington sits on Savage Grant land. The Buffington family were the only revolutionary-era claimants to live continuously in the area, and later generations of Buffingtons became associated with Marshall College and business partners of Collis P. Huntington himself. The continuity of family across centuries here is unusual for an American river town.

When Virginia voted to secede on April 17, 1861, Guyandotte's response came three days later. On April 20, men gathered outside the Planter's Hotel, where Elijah Ricketts and John W. Ong raised a secessionist flag. As W. S. Laidley rested on the sidewalk in front, a shot struck the hotel just above his head. Witnesses suspected the shot had come from across the Ohio River in Ohio - a strongly Union state. By the end of May the flag was gone. But the town's sympathies were clear. As northern and western Virginia organized to form the Union state of West Virginia, Guyandotte became increasingly out of step with its neighbors, and Union forces in the region took note.

On November 10, 1861, a Confederate cavalry force of over 700 quickly overtook a Union encampment at Guyandotte. The townspeople celebrated. Over ninety Union soldiers were captured and sent to Richmond for imprisonment. The next morning, the Confederates withdrew, and a detachment of the Fifth West Virginia Infantry arrived. In response to the townspeople's aid to the Confederates, the Union soldiers burned a large portion of Guyandotte. Houses, businesses, public buildings - much of the Federal Era town the French families had built was destroyed. The fire reflected the bitter intra-state conflict that defined this part of Appalachia during the Civil War, with neighbors who had grown up together suddenly aligned with opposite armies and willing to burn each other's homes.

What is now downtown Huntington was, before 1871, called Holderby's Landing - a smaller settlement next to Guyandotte. Marshall College, founded in 1837 as Marshall Academy - a private subscription school later transferred to the Methodist Episcopal Church, South in 1850 - was already operating there as a boarding school for sons of wealthy families. It became a public institution in 1867, then Marshall University in 1961. When Collis P. Huntington chose Holderby's Landing in 1871 as the western terminus of his Chesapeake and Ohio Railway, he platted a brand-new city around the existing settlement. The city was named for him. Within decades the new Huntington had absorbed both Holderby's Landing and Guyandotte, transforming the area from a string of small river settlements into a major industrial city.

Guyandotte today is a residential neighborhood in eastern Huntington, sitting at the confluence of the Guyandotte River and the Ohio. The Madie Carroll House and the Zachary Taylor Wellington House are both listed on the National Register of Historic Places, the surviving remnants of the Federal Era town. The eighteenth-century French-Colonial cemetery is still tended, with its LeTulle, Holderby, and Buffington headstones documenting the original settlers. Green Bottom, the plantation home of Confederate General Albert Gallatin Jenkins, sits a few miles east in Lesage, also on the National Register. The neighborhood is quieter than its history - mostly small houses on side streets, with the older buildings standing as reminders of a town that predates the city around it by more than seventy years.