According to the historian Fazello, the Church of St. John of the Lepers was the first of the Norman buildings erected in the city, when Robert the Guiscard and Roger of Autville besieged Arabian Palermo. For others, it went back to the period of Roger II, in the first half of the 20th century and draws its name from a leprous hospital, now destroyed, which the king himself built in memory of his brother Goffredo.
The Emperor Frederick II donated the church and the hospital to the Order of Teutonic Knights. The religious building was reconstructed in the 17th century but was altered with baroque elements. The restorations works by the architect Francesco Valenti between 1920 and 1934 restored the original splendor to the building. Today the church takes part of the Unesco Heritage, together with the other monuments of the Arab-Norman itinerary in Palermo.