Colonists in western Pennsylvania fled to the safety of Fort Pitt after the outbreak of the war. Nearly 550 people crowded inside, including more than 200 women and children. Simeon Ecuyer, the Swiss-born British officer in command, wrote: "We are so crowded in the fort that I fear disease...; the smallpox is among us." Fort Pitt was attacked on June 22, 1763, primarily by Delawares. The fort was too strong to be taken by force. A siege was organized, which lasted during the month of July. In the meantime, war parties raided deep into Pennsylvania, taking prisoners and killing unknown numbers of settlers in scattered farms.Too strong to be taken by force, the fort was kept under siege throughout July. Meanwhile, Delaware and Shawnee war parties raided deep into Pennsylvania, taking captives and killing unknown numbers of settlers in scattered farms. Two smaller strongholds that linked Fort Pitt to the east, Fort Bedford and Fort Ligonier, were fired upon throughout the conflict, but were never taken.
Before the war, Amherst did not believe that the Native Americans would offer any effective resistance to British rule. During that summer, he was convinced of the contrary. He ordered to "immediately ... put to death" captured enemy Native American warriors. To Colonel Henry Bouquet at Lancaster, Pennsylvania, who was preparing to lead an expedition to relieve Fort Pitt, Amherst wrote on about June 29, 1763: "Could it not be contrived to send the smallpox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them." Bouquet responded to Amherst (summer of 1763):
"P.S. I will try to inocculate [sic] the Indians by means of Blankets that may fall in their hands, taking care however not to get the disease myself. As it is pity to oppose good men against them, I wish we could make use of the Spaniard's Method, and hunt them with English Dogs. Supported by Rangers, and some Light Horse, who would I think effectively extirpate or remove that Vermine."
Amherst replied:
"P.S. You will Do well to try to Innoculate [sic] the Indians by means of Blankets, as well as to try Every other method that can serve to Extirpate this Execrable Race. I should be very glad your Scheme for Hunting them Down by Dogs could take Effect, but England is at too great a Distance to think of that at present."
Officers at the besieged Fort Pitt had already attempted to do what Amherst and Bouquet were discussing. During a parley at Fort Pitt on June 24, 1763, Ecuyer gave Delaware representatives, Turtleheart and Mamaltee, two blankets and a handkerchief that had been exposed to smallpox, hoping to spread the disease to the Native Americans in order to "extirpate" them from the territory. William Trent, the militia commander, left records that showed the purpose of giving the blankets was "to Convey the Smallpox to the Indians." Turtleheart and Killbuck would later represent the Delaware at the Treaty of Fort Stanwix in 1768.
On July 22, Trent writes, "Gray Eyes, Wingenum, Turtle's Heart and Mamaultee, came over the River told us their Chiefs were in Council, that they waited for Custaluga who they expected that Day". There are eyewitness reports that outbreaks of smallpox and other diseases had plagued the Ohio Native Americans in the years before the siege of Fort Pitt. Colonists also caught smallpox from Native Americans at a peace conference in 1759 which then led to an epidemic in Charleston and the surrounding areas in South Carolina.
Historians cannot agree how much damage the attempt to spread smallpox at Fort Pitt caused. Historian Francis Jennings concluded that the attempt was "unquestionably successful and effective" and inflicted great damage to the Native Americans. Historian Michael McConnell writes that, "Ironically, British efforts to use pestilence as a weapon may not have been either necessary or particularly effective", noting that smallpox was already entering the territory by several means, and Native Americans were familiar with the disease and good at isolating the infected. Historians widely agree that smallpox devastated the Native American population. It is estimated that 400,000–500,000 (possibly up to 1.5 million) Native Americans died during and years after the Pontiac's War, mostly from smallpox,
On August 1, 1763, most of the Native Americans broke off the siege at Fort Pitt in order to intercept 500 British troops marching to the fort under Colonel Bouquet. On August 5, these two forces met at the Battle of Bushy Run. Although his force suffered heavy casualties, Bouquet fought off the attack and relieved Fort Pitt on August 20, bringing the siege to an end. His victory at Bushy Run was celebrated in the British colonies—church bells rang through the night in Philadelphia—and praised by King George.
This victory was soon followed by a costly defeat. Fort Niagara, one of the most important western forts, was not assaulted, but on September 14, 1763, at least 300 Senecas, Ottawas, and Ojibwas attacked a supply train along the Niagara Falls portage. Two companies sent from Fort Niagara to rescue the supply train were also defeated. More than 70 soldiers and teamsters were killed in these actions, which Anglo-Americans called the "Devil's Hole Massacre", the deadliest engagement for British soldiers during the war.
The violence and terror of Pontiac's War convinced many western Pennsylvanians that their government was not doing enough to protect them. This discontent was manifested most seriously in an uprising led by a vigilante group that came to be known as the Paxton Boys. They had this name because they were primarily from the area around the Pennsylvania village of Paxton (or Paxtang). The Paxtonians turned their anger towards Native Americans—many of them Christians—who lived peacefully in small enclaves in the midst of white Pennsylvania settlements. Prompted by rumors that a Native war party had been seen at the Native village of Conestoga, on December 14, 1763, a group of more than 50 Paxton Boys marched on the village and murdered the six Susquehannocks they found there. Pennsylvania officials placed the remaining 16 Susquehannocks in protective custody in Lancaster, but on December 27 the Paxton Boys broke into the jail and slaughtered most of them. Governor John Penn issued bounties for the arrest of the murderers, but no one came forward to identify them.
The Paxton Boys then set their sights on other Native Americans living within eastern Pennsylvania, many of whom fled to Philadelphia for protection. Several hundred Paxtonians marched on Philadelphia in January 1764, where the presence of British troops and Philadelphia militia prevented them from committing more violence. Benjamin Franklin, who had helped organize the local militia, negotiated with the Paxton leaders and brought an end to the immediate crisis. Franklin published a scathing indictment of the Paxton Boys. "If an "Indian" injures me," he asked, "does it follow that I may revenge that Injury on all "Indians"?" One leader of the Paxton Boys was Lazarus Stewart who would be killed in the Wyoming Massacre of 1778.
In spring and summer of 11764, there were more Native American raids on frontier settlements that usual. The hardest hit colony that year was Virginia. In July, four Delaware Indian soldiers killed and scalped a school teacher and ten children in what is now Franklin County, Pennsylvania. Incidents such as these prompted the Pennsylvania Assembly, with the approval of Governor Penn, to reintroduce the scalp bounties offered during the French and Indian War: money was paid for every Native killed above the age of ten, including women.