The town of Oxford was incorporated in 1713. Following incorporation, town selectmen began searching for a minister. Over the next seven years, a string of short term ministers came to preach while the town figured out how to procure money to build a meetinghouse and provide the minister with salary. In July of 1720, Rev. John Campbell was called and in September of that year plans for the first meeting house were made. The First Congregational Church in Oxford (MA) was established in the house of John Campbell on January 18, 1721. He was ordained as the minister a few months later on March 1. The first meetinghouse was also likely completed in either 1721 or 1722. In 1744, it was voted to replace the simple first meetinghouse. Construction on this new meetinghouse was completed by July of 1748.

Following the death of Campbell in 1764, Rev. Joseph Bowman was called and installed as minister. He continued to serve as minister during the American Revolutionary War. During the way, the town was unable to provide Bowman with a salary. This led to some conflict between Bowman in the town which culminated in a 1784 suit and his request for dismission, which was initially rejected. As a result of the town failing to respond to the suit, the town of Oxford had to levy a special tax to pay Bowman’s unpaid salary. The first church library was founded under Rev. Elias Dudley in 1791. This library collection later became a part of the town’s public library.

The church split in 1813, following some members’ dissatisfaction with Rev. Josiah Moulton. The First Congregational Society, also known as the First Religious Society, was formed as a result of this split. They established a Universalist Church with services held at the "South Meetinghouse." The second meetinghouse, also sometimes called the "North Church," was replaced with the third, and final, meetinghouse, in 1829. In 1853, the meetinghouse edifice was moved to its present location on the town common. In 1860, the meetinghouse underwent a complete remodel and an organ was added in 1885.

On February 19, 1905, the church caught fire from an overheated stovepipe in the basement. The building’s slate room was cited as the principal reason the whole building was not destroyed. The building was repaired and rededicated on September 24, 1905. On January 11, 1961, the church adopted the constitution of the United Church of Christ. The First Congregational Church in Oxford (MA) continues to serve the local community today.