The Hospice of St. Catherine was built in 1391-92 by the Order of the Knights of St. John (Knights Hospitaller) to house and entertain esteemed guests. The Hospice built under Grand Master Heredia, by the Italian Domenico d'Allemagna, admiral of the Order of the Knights.

The Hospice, was already in use from 1394-95 one such guest, 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. In 1944 the east part of the Hospice was destroyed again by Allied bombing, along with many building in the heart of the Jewish quarter.

The restored hospice (by the Office of the Medieval Town) has exceptionally beautiful sea-pebble and mosaic floors, carved and intricately painted wooden ceilings, a grand hall and lavish bedchamber, and engaging exhibits.