This hospital founded in the 16th century has retained its function uninterruptedly since then. The germ of the building was a small hospital for pilgrims and paupers, who were cared for by the Hieronymite monks of the monastery opposite it. The Order of Hospitallers of St John of God moved into the hospital in 1551, several years after the death of their founder, who had started to prepare the move after carrying out hospital work in the city since 1539 in various buildings that always proved unsuitable.

It has two courtyards. The main one, dating from the 16th century, has two storeys connected by an interesting staircase with a Mudejar wooden ceiling. Like the rest of the building, it underwent considerable reconstruction under Fray Alonso de Jesús y Ortega, the general of the Order from 1733 to 1759. It was then that the second courtyard was built, the staircase was redecorated by José de Bada, and the iconographic programme of the first courtyard was commissioned from the artists Diego Sánchez de Sarabia and Tomás Ferrer. This was also when the Baroque basilica containing the saint's remains was built, leading to the conversion of the hospital church into an infirmary and a new entrance hall. The mannerist portal constructed in 1609 by the mason Cristóbal de Vílchez now became the main entry of the hospital.