He was orphaned at fourteen, and studied for nearly three years (1739-1742) at Yale. He then prepared for the ministry, being licensed to preach in 1742, and early in 1743 decided to devote himself to missionary work among the Native Americans. Supported by the Scottish "Society for Promoting Christian Knowledge," he worked first at Kaunaumeek, an Indian settlement about 20 miles from Stockbridge, Massachusetts, and subsequently, until his death, among the Delaware Indians in Pennsylvania (near Easton) and New Jersey (near Cranbury). His heroic and self-denying labours, both for the spiritual and for the temporal welfare of the Indians, wore out a naturally feeble constitution, and on the 19th of October 1747 he died at the house of his friend, Jonathan Edwards, in Northampton, Massachusetts.
His Journal was published in two parts in 1746 by the Scottish Society for Promoting Christian Knowledge; and in 1749, at Boston, Jonathan Edwards published An Account of the Life of the Late Rev. David Brainerd, chiefly taken from his own Diary and other Private Writings, which has become a missionary classic. A new edition, with the Journal and Brainerd's letters embodied, was published by Sereno E Dwight at New Haven in 1822; and in 1884 was published what is substantially another edition, The Memoirs of David Brainerd, edited by James M Sherwood.