Upon his return from London, Joseph Brant probably saw service with William Howe at the Battle of Long Island. Returning to Canada, he, John Johnson, and John Butler served with Barry St. Leger on his expedition to provide support to General Burgoyne. They all were involved at the Battle of Oriskany. Following the failure of St. Leger's campaign, Butler received a commission as a Lieutenant Colonel and expanded his company of rangers into a regiment, mostly composed of loyalists from New York. Butler's Rangers, working in conjunction with Joseph Brant's Iroquois, would terrorize American settlements in New York, Pennsylvania, and beyond for the rest of the war.

The Wyoming Valley in northeastern Pennsylvania had been a source of contention between rival land companies and the states of Pennsylvania and Connecticut. It was also exposed to the inroads of Indian raiding parties. The settlers had built fortified blockhouses at various points in the valley to serve as refuges when Indians were in the area.

In the spring of 1778, Colonel Butler left his base at Fort Niagara on Lake Ontario with 400 loyalists and 500 Indians. They reached the Wyoming Valley on June 30. The first notice of their coming was an attack on a party of farmers working in their fields. Soon they were taking isolated blockhouses. The Patriot Colonel Zebulon Butler gathered nearly 300 men and imprudently marched against the invaders. John Butler formed his men in line of battle and let the militia attack. After a brisk firefight the Patriots were outflanked and overwhelmed. What followed was a slaughter. Only sixty of the militia escaped. The loyalists and Indians killed all their prisoners. The Indians ritually tortured some to death. Butler reported that 227 scalps were taken that day.

This victory left the Wyoming Valley defenseless. Butler and his men swept through it, remorselessly pillaging and destroying. Butler claimed that his men burned 1,000 homes, including the entire town of Wilkes-Barre. The raiders rounded up herds of cattle, sheep, and pigs. The Indians carried off many prisoners; some settlers escaped, only to die of starvation in the wilderness. The once thriving Wyoming Valley was left a wasteland.

Frontier warfare swiftly degenerated into a seemingly endless cycle of reprisal and revenge. On September 13, Joseph Brant and a party of Indians attacked and burned the village of German Flats in the Mohawk Valley of upstate New York. As payback for German Flats, on October 8, a force of Americans burnt Unadilla, an Iroquois town.

Captain Walter Johnson decided to avenge Unadilla by destroying Cherry Valley, a village located fifty miles west of Albany with a nearby fort garrisoned by 250 Continental soldiers. He set out late in October with 200 rangers. Along the way he met Joseph Brant with 500 Indians. Brant agreed to join in the attack, and their combined forces approached the village on the morning of November 11.

The Continental defenders of Cherry Valley were unfamiliar with frontier warfare. Despite warnings from Fort Stanwix, Colonel Ichabod Alden, the commander of the fort, had rejected a request of the villagers to shelter within his stockade. He and others from the fort slept in the village.

Butler and Brant's men broke into the houses in Cherry Valley, killing or capturing the inhabitants. Alden and sixteen soldiers were slaughtered. More than thirty villagers — men, women, and children — were murdered. While the soldiers in the fort were kept occupied by musket fire, the village was plundered and then burned. On his way home, Butler released most of his captive women and children as an exchange for members of his own family, held by the Patriots.

Raids like those against the Wyoming Valley and Cherry Valley made the Butlers and Joseph Brant hated and feared. Settlers on the northern frontier called for relief from Congress, and vengeance was not long in coming.