British efforts to slow the western movement of settlement had achieved little. By the outbreak of war in 1775, American pioneers were surging into the wilderness. Daniel Boone opened a trail to Kentucky through the Cumberland Gap. He established Boonesborough early in 1775. Other settlers were penetrating into Tennessee along the Holston and Watauga rivers. Farther north, Pittsburgh and Wheeling were important way stations for pioneers moving into the Ohio River Valley. The settlement line in western Pennsylvania and upstate New York had long been contested territory. Even without Lexington and Concord, there would have been fighting along these lines of advance.

The capacity of Native Americans to resist settler encroachments on their territory was still formidable. The Six Nations of the Iroquois Confederacy had long preserved their lands in western New York and Pennsylvania through an artful combination of military power and diplomacy. The warlike Miami, Wabash, Ottawa, and Wyandot tribes guarded the vicinity of the Great Lakes. The Shawnee and Delaware formed a barrier to easy settlement along the Ohio. Farther south, the Cherokee and Creeks remained significant obstacles to American expansion.

Congress hoped to conciliate the Native Americans and sent out emissaries urging them to remain neutral. This was a forlorn hope. The British enjoyed a tremendous advantage in dealing with the western tribes. Britain could afford generous gifts and subsidies. British Indian agents had developed relations of trust and respect with many tribal leaders. Above all, the British shared the Native Americans' interest in keeping settlers east of the Alleghenies.

At the outset of the war, both sides hoped to avoid the horrors of Indian warfare. Inhibitions swiftly disappeared. Lord Dunmore in Virginia hoped to unleash a diversionary assault by Indians on the western frontier. When Massachusetts enlisted some companies of Stockbridge Indians, General Gage saw this as a pretext to urge the western tribes to go to war. He believed the use of Indians would help restore the perilous situation in Canada. He wrote John Stuart, the royal Indian agent in the south, asking him to stir the Cherokee and Creeks against the Americans.

The Cherokee had lost a war against the settlers in 1760–61. They did not need British encouragement to strike at the Americans. They launched a number of raids in the Carolinas in 1776, but they had chosen an inopportune moment to go to war. The British could offer no support to the Cherokee. Columns from Virginia, North and South Carolina, and Georgia converged on the Cherokee and forced them to surrender. Another outbreak of hostilities in 1779 led to the destruction of the main Cherokee settlements. This finished the Cherokee as a military threat.

The Creeks did not act until late in the war, nor did they press the war. The revival of Spanish power to the south raised the prospect of their being caught between two powers. The Creeks prudently concentrated on defending themselves. As a result, the southern border was much quieter than the frontier farther north.