The name Seneca derives from a Dutch word meaning the ones who live farthest out, a reference to the tribe's westernmost geographic position within the Iroquois Confederacy or Six Nations. English colonists Latinized this word, giving them the name of a Roman philosopher. The Senecas called themselves the "people of the great hill," a reference to their largest fortified village in the Genesee Valley of western New York. But it is as Seneca that this people is memorialized on West Virginia maps.

The Senecas were the most populous of the Six Nations. This, plus their traditional position as "keepers of the Western door" of the metaphorical Iroquois Longhouse, gave them leadership of the Iroquois expansion in the 17th-century Beaver Wars, conquests that underpinned the confederacy's territorial claim on the Ohio Valley and its claim to be "Chief of all the Indians" in colonial warfare and diplomacy. The Senecas were especially pivotal in their relations with the French in Canada. Initially bitterly hostile, they began to change when they captured a soldier named Louis Joncaire. Impressed by his conduct under torture, they allowed him to live and adopted him. Through his influence, the Senecas welcomed French traders and, beginning in 1726, allowed the construction of a supply base that grew into a great stone fortress at Niagara. Fort Niagara became the base for a renewed French thrust southward into the Ohio Valley. Sent by Virginia authorities to warn the French away from the region in 1753, the young George Washington was so impressed with Joncaire's importance that he returned home with a plan for his assassination.

As allies of the French, Senecas participated in the defeat of Braddock's army at the Battle of the Monongahela (1755) and in the raids on the Virginia frontier that followed. After the British emerged victorious, Senecas fought on in the coordinated uprising known as Pontiac's Rebellion (1763—66). Another defeat led to the Treaty of Fort Stanwix (1768), whereby the Six Nations ceded all lands south and east of the Ohio River, which despite Shawnee repudiation of this treaty led to an inrush of settlers into Western Virginia. During the early years of the American Revolution, Seneca leaders worked to keep the Six Nations neutral, but when three of the Iroquois nations became British allies in 1777, the Seneca joined them, attacking American posts and settlements across a wide front, including the Monongahela Valley. Following the American victory, further land cessions reduced the Seneca to a tiny reservation along the Allegheny River headwaters.

Though individual Senecas and their Mingo cousins continued fighting after 1784 as allies of the Shawnees, the warrior-statesman Cornplanter became a spokesman for peace with the Americans and for Seneca adoption of Euro-American ways. A new religion preached by Cornplanter's brother, Handsome Lake, in the early 19th century provided the basis for cultural synthesis and a modest renaissance centered on the Allegheny reservation. In West Virginia, however, only a few place names remain to mark the respect and fear that Senecas once invoked on the Ohio Valley frontier.