Neither underground nor a railroad, the Underground Railroad was a covert and loosely organized conspiracy that endeavored to aid escaped slaves on their way to Canada or safe areas in the northern states. Free African Americans, Quakers, and other White sympathizers, and other Blacks still enslaved, played the most prominent role in hiding and aiding slaves as they made their way north. As the abolitionist movement gained momentum in the mid-1800s, the Underground Railroad's activity increased. Between 1840 and 1860, it is estimated that more than a thousand slaves a year were smuggled out of the South. Three crucial junctions of the Underground Railroad existed in Virginia, at Norfolk and Richmond and in Western Virginia.

Many enslaved escaped through Western Virginia into Ohio. Under the fugitive slave law, enslaved people could be tracked and returned from anywhere in the United States, but across the Ohio River and north of the Mason-Dixon Line an escaped slave was in relative safety. Thus, the Ohio River symbolized the border of the "promised land" for many enslaved. The river ran along the western boundary of Virginia for 277 miles, a tempting destination for those who could get to it.

The majority of Ohio River crossings took place in the winter, so that those escaping could cross on ice rather than swimming or finding transportation across the river. When a winter escape was not possible, abolitionists often acquired canoes, so that the enslaved could paddle their way down the tributaries of the Ohio at night. The rugged mountains of Western Virginia also aided them as they fled north. "Slave patrols" usually avoided the Alleghenies and often confined their searches to central and Tidewater Virginia.

A number of stories about the Underground Railroad remain to this day. Ceredo was founded on the banks of the Ohio in 1857 by New England abolitionist Eli Thayer and populated by other abolitionists, and the Wayne County town soon actively participated in the Underground Railroad. It is said that Z. D. Ramsdell of Ceredo hid enslaved in his house and smuggled them through a tunnel that led from his basement to the Ohio River. Once slaves made it across the river, they could find sanctuary in the small town of Quaker Bottom, now Proctorville, Ohio. John Fairchild was a successful conductor in the Underground Railroad who often traveled back and forth across the Alleghenies, guiding numerous runaways from Virginia plantations to the Ohio River. Just east of Parkersburg, the Nutter Farm was an alleged stop in the Underground Railroad. Local stories persist that members of the Nutter family were murdered for their aid to runaway slaves.

At times, the history of the Underground Railroad is more legend than fact. Runaways often did not receive any assistance until they had escaped out of the South through their own efforts. Those who offered sanctuary and aid to enslaved people in Virginia risked severe punishment under the law and the wrath of their slave-holding neighbors, necessitating secrecy. Therefore, no substantial evidence has endured that would give modern historians exact details as to the dimensions and organization of the Underground Railroad. Most of the surviving evidence comes from the oral histories of escaped slaves and from those who boasted that they gave them aid. These oral histories often offer exaggerated accounts. Nonetheless, the Underground Railroad did exist in West Virginia and helped numerous enslaved people obtain their freedom in the years preceding the Civil War.

Some of the most detailed accounts of escapes in the Eastern Panhandle are in William Still’s The Underground Railroad (1872).