The Cherokee, after siding with the Province of Carolina in the Tuscarora War of 1711–1715,  had turned on their British allies at the outbreak of the Yamasee War of 1715–1717, until switching sides, once again, midway through the war.

This action had ensured the defeat of the Yamasee.

The Cherokee then remained allies of the British until the French and Indian War.

At the 1754 outbreak of the war, the Cherokee were allies of the British, taking part in campaigns against Fort Duquesne (at Pittsburgh, Pennsylvania) and the Shawnee of the Ohio Country.

In 1755, a band of Cherokee one hundred and thirty-strong under Ostenaco (or Ustanakwa) of Tamali (Tomotley) had taken up residence in a fortified town at the mouth of the Ohio River at the behest of the Iroquois (who are also British allies).

For several years, French agents from Fort Toulouse had been visiting the Overhill Cherokee on the Hiwassee and Tellico Rivers, and had made inroads into those places.

The strongest pro-French Cherokee leaders zre Mankiller (Utsidihi) of Talikwa(Tellico Plains), Old Caesar of Chatuga (or Tsatugi, Chatooga), and Raven (Kalanu) of Ayuhwasi (Hiwassee).

The "First Beloved Man" (or Uku) of the nation, Kanagatoga (or "Stalking Turkey", aka 'Old Hop'), is very pro-French, as is his nephew, Kunagadoga, who will succeed him at his death in 1760.

During the second year of the French and Indian War, the British had sought Cherokee assistance against the French and their native allies.

The English had reports, which proved accurate, that indicated the French were planning to build forts in Cherokee territory (as they had already done with Ft. Charleville at Great Salt Lick on the Cumberland River); Ft. Toulouse, near present-day Montgomery, Alabama; Ft. Rosalie at Natchez, Mississippi; Ft. St. Pierre at modern day Yazoo, Mississippi; and Ft. Tombeckbe on the Tombigbee River).

Once the Cherokee agreed to be their allies, the British had hastened to build forts of their own in the Cherokee lands, completing Fort Prince George near Keowee in South Carolina (among the Lower Towns); and Fort Loudoun (near Chota at the mouth of the Tellico River) in 1756.

Once the forts were built, the Cherokee had raised close to seven hundred warriors to fight in western Virginia Colony under Ostenaco.

Oconostota and Attakullakulla led another large group to attack Fort Toulouse.

In 1758, the Cherokee participate in the taking of Fort Duquesne (present-day Pittsburgh, Pennsylvania.)

However, they feel their efforts are unappreciated.

While traveling through Virginia, on their way home, several Cherokee are murdered by Virginians.

The Cherokee had been promised supplies, but misunderstood where they were to get them from.

After taking some horses they believed were rightly theirs, several Virginians had killed and scalped between thirty and forty of them.

The Virginians later claim the scalps as those of Shawnees and collect bounties for them.

While some Cherokee leaders still call for peace, others lead retaliatory raids on outlying pioneer settlements.

The Anglo–Cherokee War breaks out in 1758 when Virginia militia attack Moytoy (Amo-adawehi) of Citico in retaliation for the theft of some horses by the Cherokee.

Moytoy's reaction is to lead retaliatory raids on the Yadkin and Catawba Rivers in North Carolina, which begins a domino effect that ends with the murders of twenty-three Cherokee hostages at Fort Prince George near Keowee and the massacre of the garrison of Fort Loudoun near Chota (Itsati).

These events usher in a war that will not end until 1761.

The Cherokee are led by Aganstata of Chota, Attakullakulla (Atagulgalu) of Tanasi, Ostenaco of Tomotley, Wauhatchie (Wayatsi) of the Lower Towns, and Round O of the Middle Towns.