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The Hospice of St. Catherine was built in 1391-92, under Grand master Heredia, by the wealthy Italian Domenico D'Allemagna, Admiral of the Knights of St. John.

The foundation charter of the Hospice in 1391 states that it was «founded in the burgus of Rhodes, near the walls at the gate leading to the mole» already known as the «Gate of St. Catherine» from 1465.

The Hospice, exclusively intended for eminent guests of the Order, was already in use from 1394-95; at this date traveller Niccole de Martoni described it as «beautiful and splendid, with many handsome rooms containing many and good beds».

The building was apparently destroyed in the siege of 1480 and the earthquake of 1481. Its rebuilding, as testified by the heraldy on the west façade, was completed by Costanzo Operti in 1516, when Fabrizio del Carretto was grand master.

In 1944 the east part of the Hospice was destroyed by Allied bombing, along with many more buildings in the heart of the Jewish quarter. In the years following, the surviving part stood forlorn in a deserted neighbourhood.

Its restoration started in 1985 and lasted 15 years.