In 2015 Middlesex became the first hospital in Connecticut to join the Mayo Clinic Care Network.

In 1895 the Connecticut General Assembly issued a charter incorporating Middlesex Hospital.

With a $20,000 grant from the state, and the gift of the Camp Homestead on Crescent Street, the hospital opened in the spring of 1904.

In addition to its emergency department in Middletown, the health system operates two satellite medical centers in Westbrook, Connecticut, and Marlborough, Connecticut, with fully accredited, stand-alone emergency departments.

Combined, the three locations serve the 4th highest emergency patient volume of all Connecticut hospitals.

[9] In 2018, Middlesex Hospital earned a "Leader in LGBTQ Healthcare Equality" designation from the Human Rights Campaign Foundation.