Brant was born to a Mohawk chief in 1742 on the banks of the Ohio River, and was named Thayendanegea, or "he places two bets." As a teenager he became an interpreter for an Anglican missionary named John Stuart, with whom he translated the Gospel of Mark into the Mohawk language. His sister Molly married General William Johnson, the British superintendent for Indian Affairs, and with whom Joseph fought in the French and Indian War.
During the American Revolution he led the remaining four of the Six Nations who had sided with Britain, becoming a captain in the British army. He was defeated by General John Sullivan in 1779. After the war, he was unable to secure land transfers for the natives from the newly created American government; instead, the British gave him land for a Mohawk reservation on the Grand River in Ontario. He acted as a missionary to the other natives, building the first Anglican church in Ontario and attempting to translate the Bible into Mohawk. He died in the reservation on August 24, 1807. The city of Brantford, Ontario, located on part of his land grant, is named for him.