The Indians of the Northwest Territory were emboldened at the end of the War of Independence by the retention of British forts in Northern Ohio. The Americans believed that the Indians had forfeited their land claims due to their support for the British. However, the Americans attempted to reach agreements with the tribes, but not all were willing to negotiate. Among the opponents were the Miami Indians, who were determined to expel the White settlers from their lands. Throughout the spring and summer of 1790, the Miami Indians launched scattered attacks throughout Northern Ohio. The governor of Ohio sent Major John Hamtramck to investigate and assess the plans of the Miami and other tribes. He returned with a warning that the tribes were planning to wage war against the settlers.

The governor of the Ohio territory dispatched expeditions under the command of Colonel James Hardin and James Trotter, which achieved little. The Americans proved incompetent, only managing to burn down some tribal villages, further enraging the tribes.

The military action gave the settlers a false sense of security, leading them to continue settling. The most vulnerable settlement was Big Bottom, located 40 miles further upstream than any other. Eleven families had begun to settle the area. On the night of January 2, 1791, the Miami attacked the settlement, annihilating it and killing all the settlers: men, women, and children. This incident became known as the Big Bottom Massacre.

The massacre compelled the U.S. government to act. President Washington appointed St. Clair, the governor of the territory, to lead a force to defeat the Native Americans. In late September, St. Clair set off from Cincinnati with twenty-three hundred regulars and militia. Along the way, he first built Fort Hamilton, then Fort Jefferson forty miles down the Ohio River. After a further ten-day march, during which he lost almost half his men to attrition, St. Clair reached what he believed was the St. Mary River, but was actually a branch of the Wabash. There, he deployed his men in search of the Native Americans, who were reported to be plentiful in the woods. On the morning of November 4, 1781, the warriors attacked. The outnumbered American regulars, using conventional tactics, struggled against the Native Americans in the wooded terrain. The Indians gradually gained the upper hand, scalping captured Americans in view of their comrades, spreading fear among the U.S. forces. Ultimately, St. Clair decided their only option was to fight their way out. Managing to break free from the Indian warriors, they left behind their equipment and wounded, and retreated hastily to Fort Jefferson. The retreat, covering in ten hours what had taken ten days the week before, marked a humiliating defeat for the American Army.