Middletown was one of the most important ports on the Connecticut River during the colonial period, and Main Street "has been the center of community life since the earliest period of settlement".

[2] Today Main Street is home to a number of 19th century buildings, maintaining the bulk of its historic character.

[1] The district extends along Main Street from St. John's Square (junction with Spring Street) in the north, for five blocks on the west side (to College Street) and 4-1/2 blocks on the right (midway between Washington and Court Streets), abutting the Metro South Historic District on the west side, and modern buildings on the right.

[2] According to the National Register of Historic Places (NRHP) nomination for the district, two properties in the district—the Church of the Holy Trinity and the Old Middletown Post Office are already on the NRHP in their own right.

More generally, the entire block on the east side of Main Street from Washington to Ferry Streets, and numbers 560-614 from Ferry to Green were determined to be eligible.