Outside the "pays d'en haut", most warriors of the influential Iroquois Confederacy did not participate in Pontiac's War because of their alliance with the British, known as the "Covenant Chain". However, the westernmost Iroquois nation, the Seneca tribe, had become disaffected with the alliance. As early as 1761, the Seneca began to send out war messages to the Great Lakes and Ohio Country tribes, urging them to unite in an attempt to drive out the British. When the war finally came in 1763, many Seneca were quick to take action.
General Amherst was the British commander-in-chief in North America. He was also responsible for the policy regarding the treatment of Native Americans. This involved both military matters and the regulation of the fur trade. In Amherst's opinion, the Native Americans had to accept British rule, since the French were no longer in control of the territory. He also believed that they were incapable of resisting against the British Army; therefore, of the 8,000 troops under his command in North America, only about 500 were stationed in the region where the war erupted. Amherst and officers such as Major Henry Gladwin, commander at Fort Detroit, made little effort to conceal their contempt for the Native Americans. Native Americans involved in the uprising frequently complained that the British treated them no better than slaves or dogs.
In February 1761, Amherst took the decision to offer fewer gifts to the Native Americans. With the French, the giving of gifts had been common, and part of the relationship between French and Native Americans. Therefore, Amherst's decision led to more resentment towards the English. Following a Native American custom the exchange of gifts had an important symbolic meaning: the French gave presents (such as guns, knives, tobacco, and clothing) to village chiefs, who in turn redistributed these gifts to their people. By this process, the village chiefs gained stature among their people, and were able to maintain the alliance with the French. Amherst, however, considered this process to be a form of bribery that was no longer necessary, especially since he was under pressure to cut expenses after the war with France. Many Native Americans regarded this change in policy as an insult and an indication that the British looked upon them as conquered people rather than as allies.
Amherst also began to restrict the amount of ammunition and gunpowder that traders could sell to Native Americans. The French had always made these goods available. Amherst, however, did not trust the Native Americans, particularly after the "Cherokee Rebellion" of 1761. In this rebellion Cherokee warriors took up arms against their former British allies. The Cherokee war effort had collapsed because of a shortage of gunpowder. Amherst therefore hoped that future uprisings could be prevented by restricting the supply of gunpowder. This created resentment and hardship: Native American men needed gunpowder and ammunition, because it helped them with hunting. With gunpowder and ammunition, they had more game for their families and skins for the fur trade. Many Native Americans began to believe that the British were disarming them before starting war against them. Sir William Johnson, the Superintendent of the Indian Department, tried to warn Amherst of the dangers of cutting back on gifts and gunpowder, but he was not successful.
Land was also an issue in the coming of the war. With the French, there were relatively few colonists. Most of the colonists were farmers, who also traded fur during the hunting season. In contrast, there were many British colonists. The British colonists wanted to clear the land of the trees and occupy it. Shawnees and Delawares in the Ohio Country had been displaced by British colonists in the east: This was the main reason for their involvement in the war. On the other hand, Native Americans in the Great Lakes region and the Illinois Country had not been greatly affected by white settlement. They were aware of the experiences of tribes in the east, though. Historian Gregory Dowd argues that most Native Americans involved in Pontiac's Rebellion were not immediately threatened with displacement by white settlers. Dowd argues that historians have therefore overemphasized British colonial expansion as a cause of the war. He believes that the presence, attitude, and policies of the British Army, which the Native Americans found threatening and insulting, were more important factors.
Another factor that led to the outbreak of the war was a religious awakening of the Native Americans in the region in the 1760s. Food shortages and epidemics, as well as discontent with the British fed the movement. The most influential person in this phenomenon was Neolin, known as the "Delaware Prophet". Neolin said, Native Americans should steer clear of the trade goods, alcohol, and weapons of the whites. Merging elements from Christianity into traditional religious beliefs, Neolin told listeners that the Master of Life was displeased with the Native Americans for taking up the bad habits of the white men, and that the British posed a threat to their very existence. "If you suffer the English among you," Neolin said, "you are dead men. Sickness, smallpox, and their poison [alcohol] will destroy you entirely." It was a powerful message for a people whose world was being changed by forces that seemed beyond their control.
Although fighting in Pontiac's Rebellion began in 1763, rumors reached British officials as early as 1761. According to these rumors, discontented Native Americans were planning an attack. Senecas of the Ohio Country (Mingos) circulated messages ("war belts" made of wampum) which called for the tribes to form a confederacy and drive away the British. The Mingos, led by Guyasuta and Tahaiadoris, were concerned about being surrounded by British forts. Similar war belts originated from Detroit and the Illinois Country. The Native Americans were not unified, however, and in June 1761, Native Americans at Detroit informed the British commander of the Seneca plot. After William Johnson held a large council with the tribes at Detroit in September 1761, peace was maintained, but war belts continued to circulate. Violence finally erupted after the Native Americans learned in early 1763 that the French would give the "pays d'en haut" to the British.
The war began at Fort Detroit under the leadership of Pontiac. It quickly spread throughout the region. Eight British forts were taken; others, including Fort Detroit and Fort Pitt, were unsuccessfully besieged. Francis Parkman's "The Conspiracy of Pontiac" portrayed these attacks as a coordinated operation planned by Pontiac. Parkman's interpretation remains well known. Other historians have since argued that there is no clear evidence that the attacks were part of a master plan or overall "conspiracy". The most common view among scholars today is that, rather than being planned in advance, the uprising spread as word of Pontiac's actions at Detroit traveled throughout the "pays d'en haut", inspiring already discontented Native Americans to join the revolt. The attacks on British forts did not happen at the same time: most Ohio Native Americans did not enter the war until nearly a month after the beginning of Pontiac's siege at Detroit.