The first people known to occupy the territory of present West Virginia were the Paleo-Indians, who were here by 10,500 B.C. After that, the region was continuously occupied by native people until the 17th century. At that time, just before the encroachment of Americans of European descent, the native population disappeared from the area now comprising West Virginia. The first white visitors found the region empty of settled population. The reasons are unclear, but probably included tribal conflict and the European diseases traveling ahead of white settlers.

By the time the first settlers arrived, the native villages on the Ohio, Kanawha, and Monongahela rivers were abandoned. Archeologists have not been able to relate these villages to tribes known from the historic period. (The historic period is the period for which written records are available, beginning with the appearance of white explorers.) The historic tribes most closely associated with Western Virginia are the Shawnee, Delaware, and Cherokee, as well as Iroquoian-speaking groups including the Seneca, Tuscarawas, Susquehannock, and Mingo. Non-resident Indians were present on a frequent but intermittent basis during the early historic period, using the region for hunting and travel and fiercely resisting its settlement by whites. At various times this region was within the spheres of influence of the powerful Iroquois Confederation to the north, the Shawnees to the west, and the Cherokees to the south. Their impact on our history was profound.

With no resident native population at the time of white settlement, West Virginia now has no federally recognized American Indian tribes or tribal lands. Indians present here today originated elsewhere or descend from people who did, as do all other West Virginians. As a consequence, the state's small Indian population is richly diverse, from many tribal backgrounds. The 2010 census listed 3,787 Indians (officially "American Indians and Alaska Natives") living in West Virginia. Additionally, 9,527 people were of American Indian ancestry in combination with other races in 2010. The total figure of Indians plus the category of mixed ancestry was 13,314, or 0.7 percent of the state's population, in 2010.

Many West Virginians claiming partial Native American or Indian ancestry claim it through the Cherokee, often a maternal ancestor. There are important reasons for this. Identification with the Cherokee over other Indian tribes is in many cases probably due to the greater familiarity with the Cherokee. They were one of the largest and most powerful tribes in the Southeast and a factor in Western Virginia throughout the frontier era. As for gender, it was culturally easier for Indian women to marry white men than for Indian men to marry white women. Further, most tribes in Appalachia were matrilineal, with descent and inheritance traced through the mother rather than the father.

There are also several tri-racial groups in West Virginia, apparently combining Caucasian, African-American, and Indian ancestry. These groups include the so-called Guineas (sometimes considered to be an offensive term), the Melungeons, and descendants of the Buffalo Ridge Cherokee. The Allegheny Indian Council and Cultural Center, located in Philippi, was founded about 1979. This group includes members sometimes referred to as Guineas, although some members prefer to assert an Indian identity. The organization has been successful in receiving education grants through the Indian Manpower Program operated by the Three Rivers Indian Center in Pittsburgh.

While most common in the mountains of Virginia and Tennessee, Melungeons were reported living in the upper reaches of Bluestone Reservoir before the land was purchased by the federal government. Surnames often held by Melungeons are common throughout southern West Virginia. The United Cherokee Indian Tribe of West Virginia is a tri-racial group that has members of Cherokee and Eastern Siouan descent. It is a branch of the Buffalo Ridge Cherokee, a tri-racial band in Amherst County, Virginia, whose members can trace their Eastern Siouan ancestry back to the late 1600s.

Many of the Native Americans now living in West Virginia are from tribes outside Appalachia, and have come here for the same myriad of reasons that people of other ethnic groups have. Indian mobility increased in the mid-20th century. The Bureau of Indian Affairs began its relocation program in 1954, and more Indians began moving off reservations to other areas. While large concentrations of American Indians remain on the major reservations, especially in the West, others live throughout the country and relocate for employment, retirement, and other reasons.

West Virginia Indians are organized into several groups. The largest, the Appalachian American Indians of West Virginia, has approximately 2,500 members, representing 43 different tribes or blood lines. These include tribes as diverse as the Lakota, Blackfoot, Apache, Navaho, Choctaw, Cree, and Aztec. The group is also known as the Appalachian Nation of Indians. It holds regional meetings across the state and promotes public awareness, education and outreach, social activities, and festivals.

Other native organizations include the West Virginia Native American Coalition; the People of the Earth Organization, of South Charleston; the Native American Indian Federation, of Huntington; the Native American History Council; and the Organization for Native American Interests, at West Virginia University.

West Virginians participate in cultural practices now common to Indians throughout the country. In the 20th century the term powwow became commonly used to designate Native American music and dance events. A powwow circuit was organized and today includes powwows sponsored by Indian organizations in West Virginia. These powwows are modeled after Plains Indian celebrations and include dancing, singing, native crafts, and foods such as fry bread, buffalo, venison, and other wild game. Traditional dances such as the Grass Dance, Hoop Dance, and Eagle Dance are performed, depending on the skills and status of the principal dancers. Indians participate as well in the annual Vandalia Gathering at the state capitol complex and at other events.