In 1871, the National Council of Congregational Churches in the United States came into being as a formal denomination in which First Church participated. In 1957, that denomination merged with the Evangelical and Reformed Church, a German Lutheran denomination, to become the United Church of Christ (UCC). Because individual Congregational churches are legally independent, each church had to vote to join the UCC. Some never joined, but, four years after the UCC was formed, Wethersfield's First Church congregation did vote to join the new denomination.

By the mid-1990s, the UCC's primary focus and some of its theology had veered away from First Church's mission and vision. At a congregational meeting in 2004, almost 90% of those present (well over the required two thirds) voted to disassociate from the UCC, terminating that denominational tie.

First Church maintains special relationships with many other Christian organizations, such as Vision New England, an organization uniting Christians for evangelism, discipleship, and celebration; Compassion International; and World Vision. First Church continues in the Congregational tradition but is not formally joined with any organized denomination.