At the end of the 1960s, Wiesbaden's city council decided to unite the municipal hospitals under one roof and build a central hospital. On 15.11.1973, the city council made the decision in favor of the approximately 22-hectare site on the Freudenberg.

Following the purchase of the site from the federal government and six years of construction, the new main building was occupied on October 18, 1982. The clinic was named after the Hessian Minister of Social Affairs, Dr. Horst Schmidt. In 1984, the children's clinic opened, which is still considered one of the most modern and beautiful children's clinics in Germany in architectural terms. A neurosurgery clinic was opened in 1992, followed by a training center the following year. This was followed by the construction of the psychiatric clinic in the south of the site with over 94 inpatient beds, a day clinic and a psychiatric outpatient clinic. This was followed by the construction of the new Institute for Laboratory Diagnostics and Hygiene and the Institute for Pathology and Cytology and the relocation of the intensive care unit in 2010.

The Helios Dr. Horst Schmidt Clinics are an academic teaching hospital of Johannes Gutenberg University Mainz and, as a central care hospital, have 24 specialist departments and four institutes. One focus of its work is on treatment and scientific research in the field of oncology.

The Helios Dr. Horst Schmidt Clinics were taken over by Rhön Klinikum AG in 2012 and by Helios Region Hessen in 2014. The question of a new building for the HSK is currently on the agenda.