St. Joseph's Hospital began a few years after the construction of St. Boniface and is also closely linked to the fortunes of the church due to the building's origins. The nucleus of St. Joseph's Hospital is the branch institute of the Poor Handmaids of Jesus Christ (ADJC).

Initially three, later seven so-called Dernbach Sisters came to Wiesbaden in 1856 to expand outpatient nursing care. With funds from the Vinzenzverein and private donations, a former residential building with a rear building and garden on the grounds of the Catholic parish in Friedrichstraße was acquired and the sisters moved in on October 1, 1862. In the same year, Duke Adolph zu Nassau granted the sisters corporate rights and the name "Filialinstitut der Armen Dienstmägde Jesu Christi" (Filial Institute of the Poor Handmaids of Jesus Christ). In 1876, the house, which had temporarily served as a military hospital during the war of 1870/71 and then as a school, was converted into a hospital for the inpatient accommodation of patients.

By 1884, a new four-storey building in the neo-Gothic style, the Hospital zum HeiligenGeist (Hospice of the Holy Spirit), had been built. But even this building soon became too small; the new St. Joseph's Hospital at its current location was inaugurated on August 15, 1892. From then on, surgical cases were treated here and all patients with internal ailments were treated in the hospice. After the First World War, during which St. Josefs-Hospital was once again used as a military hospital, the gynecology department was further expanded, with its own maternity ward from 1925. The first secular nurses were appointed in 1930.

Heavily damaged by a bomb in February 1945, planning for a new building began in the late 1950s and was completed by 1965. The St. Josefs-Hospital now had all the facilities of an acute care hospital, which is why the old Hospice zum Heiligen Geist was demolished in 1969.

Further extensive construction work began in 2002, and in 2004 the Orthopaedic Clinic Wiesbaden found its home in the newly built west wing. In 2014, the last convent of the Poor Handmaids of Jesus Christ was dismissed from St. Joseph's Hospital, which resulted in a change in the supporting structure. Since then, the St. Josefs-Hospital Wiesbaden Foundation, a foundation under civil law, has been the sponsor.