[4] The St. Francis Hospital might have been established as early as 1299, and a register held at the Vatican Apostolic Archive suggests that it already functioned during the reign of King Frederick the Simple of Sicily in the second half of the 14th century.

[2] In 1433, King Alfonso ordered the Università to run and maintain the hospital, while recognising the jurisdiction of the Bishop of Malta over it.

[5][7] 15th and 16th century records from the hospital are preserved at the Mdina Cathedral Museum, and they are a primary source about late medieval and early modern Malta.

The building was restored during the 17th century, and in 1688 its church (also dedicated to the Holy Spirit) was reconstructed under the auspices of Grand Master Gregorio Carafa.

[2] The building was subsequently left in a derelict state for a number of years,[3] until efforts to repurpose it were made in the 1980s with various possible uses being considered, including conversion to a medical museum or an old people's home.

[1] Part of the archive was transferred from the Grandmaster's Palace in Valletta to the former hospital by 28 July 1989, and the building was officially opened by President Ugo Mifsud Bonnici on 28 May 1994.