Wheelock also acted as an itinerant preacher during the Great Awakening, a religious revival that had begun to sweep the Connecticut River Valley around the time of his graduation from Yale.

In addition, Wheelock was deeply concerned about Native Americans in New England, whose numbers had declined rapidly due to disease, warfare and social disruption, including continued encroachment on their lands by colonists.

He taught Occom for four years; the youth was a ready student, learning to read and write in Hebrew as well as deeply studying theology.

After preaching for several years to the Pequot people in Montauk on eastern Long Island, Occom was ordained in Suffolk County, New York, as a Presbyterian minister.

Wheelock's success in preparing Occom for the ministry encouraged him to found a school in Columbia, Connecticut, for Native Americans.

After sending Occom and another minister on a speaking tour of England to raise money for the charity school, Wheelock decided to enlarge it, as well as adding college classes for the education of American colonists in the classics, philosophy, and literature.

Having worked and raised funds for the education of Native Americans, Occom and the British Board of Trustees headed by Lord Dartmouth opposed the addition of the college to benefit the sons of the colonists.