The building that today houses São José Hospital was ordered built starting in 1579, under the patronage of Cardinal Henry of Portugal, to house the College of Saint Anthony the Great (Colégio de Santo Antão), an important Jesuit-run educational institution that was up until then located in the Mouraria quarter.

On 1 November 1755, a large-scale earthquake followed by a tsunami and a firestorm destroyed much of the Lisbon downtown, where the central Royal Hospital of All Saints was located.

It was around this time that tensions between the Portuguese crown and the Jesuits came to an all-time high after King Joseph I's chief minister, Sebastião José de Carvalho e Melo (later, and today best known as, the Marquis of Pombal), implicated them in the Távora affair.

In 1759, the Jesuits were expelled from Portugal and its dominions, and the Portuguese crown seized their assets — among them, the College of Saint Anthony the Great.

Due to financial constraints, All Saints' Royal Hospital was never fully rebuilt.