He was born in Bedford, England. He came to Pennsylvania in 1754, and, after finishing his education, was apprenticed to a cooper. After a visit to Ohio with Christian F. Post, a colonial agent, in 1762, and temporary employment in the Moravian missions at Friedenshütten and Sheshequin, Pennsylvania, in 1765-1771, he entered, in the latter year, upon his actual career as an evangelist to the Indians, being appointed assistant to David Zeisberger, in Ohio, where he remained fifteen years. In 1792, at the request of the secretary of war, he accompanied Gen. Rufus Putnam to Post Vincennes to treat with the Indians. In 1793 he was a second time commissioned to assist at a treaty with the Indians of the lakes. In his book, Heckewelder explained the beliefs of the Delaware (Lenape), that the creator "made the Earth and all that it contains for the common good of mankind; when he stocked the country that he gave them with plenty of game, it was not for the benefit of a few, but of all; everything was given in common to the sons of men. Whatever liveth on the land, whatsoever groweth out of the Earth, and all that is in the rivers and waters was given jointly to all and everyone is entitled to his share. From this principle hospitality flows as from its source." Between 1797 and 1800 he remained mainly in Ohio, and was for a time in the civil service, being a postmaster, a justice of the peace, and an associate justice of the court of common pleas. He settled at Gnadenhütten, Ohio, in 1801, and devoted himself to the duties of his agency, but resigned in 1810 and engaged in literary pursuits in Bethlehem, Pennsylvania, till his death.
He studied carefully the languages, manners, and customs of the Indians, particularly the Delawares, and after he had become a member of the American Philosophical Society, at Philadelphia, several of his contributions of Indian archaeology were published in their transactions. He also published Account of the History, Manners, and Customs of the Indian Nations who once inhabited Pennsylvania and the Neighboring States (Philadelphia, 1818; German translation, Göttingen, 1821; French translation, Paris. 1822); Narrative of the Mission of the United Brethren among the Delawares and Mohegan Indians (Philadelphia, 1820); and a collection of Names which the Lenni Lenape or Delaware Indians gave to Rivers, Streams, and Localities within the States of Pennsylvania. New Jersey, Maryland, and Virginia, with their Signification (1822). Many of his manuscripts are in the collections of the Historical Society of Pennsylvania.