In 1775 he headed to Tyron County Committee of Safety, and became Colonel of the county militia. After the split in which loyalist militia members from the area withdrew to Canada, he became a Brigadier General in the State militia. When he learned of the siege of Fort Stanwix to the west in late July of 1777, he ordered the county militia to assemble at Fort Dayton.
See main article: Battle of Oriskany
He then marched them out to relieve Fort Stanwix, about 28 miles to the west. His force was ambushed on August 6 by a mixed force of British regulars, Tory Militia rangers, and Mohawk Indians in the Battle of Oriskany. Herkimer's horse was shot, and he was seriously wounded. In spite of his injuries, he sat propped against a tree and lit his pipe. He rallied his men to avoid two panicked retreats, and when they withdrew they carried him home. His leg was amputated, but the operation went poorly and he died of the injury on August 16.
His home, in what is now Danube, New York, is preserved as a state historical park. Herkimer County, New York was named in his honor. His nephew John Herkimer later became a U.S. Congressman.