Brűlé travelled to New France in 1608 and was sent by Samuel de Champlain to live with the Huronss in 1610, where he learned their language and customs. He became a scout for Champlain and explored much of Quebec, what is now Ontario, and what is now Michigan, and he is known as the first coureur de bois ("runner of the woods"). He was probably the first European to see Lake Huron, Lake Ontario, Lake Erie, and Lake Superior, and he also travelled as far south as the Chesapeake Bay. On the way back to Quebec he was briefly captured and tortured by the Iroquois.
Champlain and the Jesuits often spoke out against Brűlé's adoption of Huron customs, as well as his association with the fur traders, who were beyond the control of the colonial government. Brűlé left Quebec to live with the natives in the 1620s. As he had no longer had any particular loyalty to Champlain or the French, Brűlé helped the English capture Champlain and Quebec City in 1629 (though the colony was returned to France in 1632).
He was killed, and eaten, by the Hurons after an argument in 1632.