The Middletown Scientific Association was founded on March 17, 1871 by Wesleyan University faculty and residents of Middletown, Connecticut. Its purpose was to encourage scientific investigation and curiosity among members and to receive papers from members and other scientists regarding popular topics in all fields of science, history of science, and education of science. The association was one of the very first town and gown organizations at Wesleyan University. Founding members included John Johnston, E. P. Barrows, Frederic Gardiner, R. G. Pike, H. D. A. Ward, J. M. Van Vleck, J. C. Van Benschoten, W. N. Rice, C. T. Winchester, G. Browne Good, Noah Cressy, E. B. Nye, G. W. Burke, W. W. Coe, H. E. Sawyer, J. H. Emerson, F. D. Edgerton, J. P. Taylor, S. W. Noyes, F. H. Newhall, C. S. Harrington, Joseph Cummings, A. M. Shew, and A. W. Hazen. Members of the association, in addition to Wesleyan faculty, included physicians, ministers, and teachers. Women were admitted into membership beginning in 1880.

Regular meetings were often held in the Hall Laboratory of Chemistry, Scott Laboratory of Physics, and Shanklin Laboratory of Biology at Wesleyan University. Occasional field meetings were held, during which members would learn first-hand about botany, geology, and other topics of natural history. Early in the association's history, papers were given at regular meetings on a variety of scientific topics in all fields, usually by members of the association, and occasionally by outside scientific experts. As membership grew, lecturers were more frequently invited from abroad to speak to the association.

The Middletown Scientific Association disbanded in 1968, after attendance at regular meetings was limited to those members who had been invited to dinner to meet with the lecturer. Though membership numbers and satisfaction with the organization remained high, there appeared to be a consensus among members that individuals were too busy to attend. The final meeting was held on April 8, 1968.