The Missionary Society was organized on May 29, 1799 in Boston, Massachusetts, with thirty-eight charter members, most of them orthodox Calvinists opposed to Unitarianism. The Society was created to spread "knowledge of the glorious Gospel of Christ among the poor Heathen and in those remote parts of our country in which the inhabitants had not enjoyed the benefits of a Christian ministry and Christian ordinances"—primarily Maine and New York State. Nathaniel Emmons was the first President of the Society. In 1827 the Massachusetts Missionary Society and the Domestic Missionary Society of Massachusetts Proper (founded in 1818), were united under the name of the Massachusetts Missionary Society; consequently, their work was concentrated specifically in Massachusetts. The Massachusetts Missionary Society became the Massachusetts Home Missionary Society in 1844. The new title emphasized its primary mission of supporting Congregational churches within the United States, and Massachusetts in particular.

The General Association of Massachusetts Proper came into being in 1808 to support the work of the newly formed American Board of Commissioners for Foreign Missions. This ultimately became the Massachusetts Congregational Conference in 1907. The Conference then merged with the Massachusetts Home Missionary Society in 1927, to become the Massachusetts Congregational Conference and Missionary Society. This merger was the result of twenty-seven years' of agitation by various members, and accelerated by a recommendation of the National Council of Congregational Conferences in 1907. The charter of the Massachusetts Home Missionary Society was used as the basis for the union of the two organizations. In 1953 the name was changed to the Massachusetts Congregational Christian Conference, and in 1966 the name was changed again to the Massachusetts Conference of the United Church of Christ, as it remains to the present.