In the 15th century, the first European hospital to receive mental patients was created in Valencia at the initiative of the Mercedarian Brother Gilabert Jofre.

Saint Mary of the Holy Innocents and Forsaken is the patroness of the hospital, whose image, Our Lady of the Forsaken, is the main centre of devotion to the Mother of God in Valencia and inspires a deep social and charitable sense of religiosity of the Valencians.

In that same century, specifically in 1437, King Alfonso V the Magnanimous gave the Cathedral of Valencia the reliquary of the Crown of Aragon, among whose treasures the Holy Chalice of the Last Supper of the Lord, stands out, which had been preserved in the Monastery of San Juan de la Peña (Huesca) until 1399.

Rome and Valencia are closely related in this period thanks to the Borgia family, a family of Aragonese origin established in Xátiva, from which Alfonso Borgia, Bishop of Valencia and cardinal, came from, who was elected Pope with the name of Callixtus III in 1455; his nephew Rodrigo Borgia was his successor in the Valencian see and held Peter’s see in Rome since 1492, under the name of Alexander VI.

Shortly before, the Church of Valencia was elevated to the rank of metropolitan, detaching itself from Tarragona, having as its first suffragans the dioceses of Mallorca, Menorca, Segorbe and Cartagena.

The memory of Callixtus III is linked to his personal effort to save Europe from the Turkish invasion, which culminated in the victory of Belgrade; he also ordered a new trial for Joan of Arc in 1456 and canonized Saint Vincent Ferrer.

Alexander VI supported Isabella the Catholic by giving evangelizing meaning to the discovery of America and was the arbitrator of the allocation of the Atlantic territories between Spain and Portugal.

In the 16th century, another Valencian Borgia, the former 4th Duke of Gandia, Saint Francis Borgia (+ 1572), would be the second successor of Saint Ignatius of Loyola as General of the Society of Jesus.