After graduating from Yale University in 1765, Cutler worked as a schoolteacher, whaling merchant, and lawyer. In 1768 he began to study divinity and in 1771 was ordained a minister at Ipswich Hamlet. Later he supplemented his ministry by practicing medicine and conducting a private boarding school.

Cited for heroism as an American Revolutionary War chaplain, Cutler joined with other veterans of the war in Boston in 1786 to form the Ohio Company of Associates in order to develop the Ohio Valley. The veterans hoped to use their depreciated Continental certificates at par value for the purchase of a large tract of land.

Cutler, selected as the company's negotiating agent, obtained a contract with the Continental Congress for the purchase of 1,500,000 acres (610,000 hectares) of public land around Marietta, Ohio. The company sent out colonists from New England, and Marietta, the first permanent settlement in the present state of Ohio, was founded in 1788. It has frequently been claimed that Cutler also acted as a leading author of the Northwest Ordinance of 1787, particularly of its paragraphs prohibiting slavery and encouraging public education. Among his other achievements were his election to Congress as a Federalist (1801–05) and to various learned societies, and his investigations in astronomy, meteorology, and botany.