MRH began with the privately owned Medina Hospital, which was located at 1705 21st Street in Hondo. In the early 1960's when the elderly owners decided to close the old hospital, a group of community leaders decided that a new hospital facility was needed. The concept was put to the voters of Medina County, and after an initial defeat, Medina Memorial Hospital was approved. The hospital is located on a 6.8 acre site in southeast Hondo. Half of the financing for the original structure was arranged through the Federal Hill-Burton Act program, and the other half from county and city funds. The first Board of Managers included John H. Poerner, Chairman, Louis E. Hart, Vice Chairman, William E. Berger, Secretary/Treasurer, Robert Zuberbueler, Hilmar b. Haegelin, Edgar Stiegler and J. Travis Lilly.

Additions in 1983, 1986 and 1989 have increased service in the outpatient and emergency services department. In 1987 the hospital's name was changed from Medina Memorial to Medina Community Hospital to better reflect the hospital's role in serving Medina County and the surrounding area.

In 2001, Medina County and the City of Hondo began discussions for the transfer of ownership to a new Municipal Hospital Authority. On December 1, 2002, the assets of Medina Community Hospital were transferred to the Hondo Hospital Authority. The Authority's nine-member Board of Directors was appointed by the City of Hondo. In November 2006, the construction phase began on a two-year expansion and renovation plan to modernize the facility.

The first phase opened in January 2008 with the final phase completed in February 2009. With the grand opening of the new facilities, the Board of Directors voted to change the name of the hospital to Medina Regional Hospital to emphasize its commitment to the health of the entire Medina County region. In June 2009, voters approved the creation of a hospital tax district to support the future of healthcare in the county. Prior to this, the hospital was funded solely by revenues from operations, state and federal funding and grants, and revenue bonds.

Effective October 1, 2009, the Medina County Hospital District will replace the Municipal Hospital Authority as the owner of Medina Regional Hospital and the Medina Healthcare System. The Medina County Hospital District will also assume responsibility for the Medina County Indigent Healthcare Program. The temporary Board of Directors approved with the creation of the hospital tax district are: Carlton "Corky" Young, President; Steve Hackebeil, Vice President, Lisa Rothe,Secretary/Treasurer; Rita Vance, Judy Winkler, Mario Garcia and Tima Barrientes. A county election for the seven board member positions will be held in May 2010.

Medina Regional Hospital is one of the larger employers in the county, and a major contributor to the local economy. MRH employs a total of 190 full and part-time employees with an annual payroll of $4.6 million. The hospital and clinics employ a variety of professionals, from physician assistants, certified health technicians and varying levels of skilled nursing staff, to hospital management, administrative support, billing specialists, clerical staff, dietary, housekeeping and maintenace personnel.