The Jesuits arrived in Palermo in 1549, and by the late 16th century began building a church adjacent to their professed house (casa professa) based on a design by the Jesuit architect Giovanni Tristano. The original design called for a single nave with large transepts and several side chapels, but the building was refurbished in starting in the early 17th century, to a more grandiose layout typical of Jesuit architecture. Natale Masuccio removed the chapels' dividing walls to add two side naves to the central one. The dome was completed in 1686.

The interior also received new decorations, starting in 1658 but continuing well into the next century. This baroque decor included marble bas-reliefs on the tribuna depicting the Adoration of the Shepherds (1710–14) and Adoration of the Magi (1719–21), by Gioacchino Vitagliano, after designs attributed to Giacomo Serpotta - both reliefs survive. A fresco of the Adoration of the Magi was also added to the walls of the second side-chapel to the right by Antonino Grano in the 1720s. The church also contains a relief of the Glory of St Luke by Ignazio Marabitti. Much of the interior stucco decoration was completed by Procopio Serpotta, son of Giacomo.

In 1892, cavaliere Salvatore Di Pietro, philanthropist, former rector of the Casa Professa, prefect of studies at the seminary, and member of the Theological College, of the Academy of Sciences, letters and arts and of the Accademia di storia patria, convinced in 1888 the minister of public education, Paolo Boselli, to decree the church a national monument.

In 1943, during the Second World War, a bomb collapsed the church's dome, destroying most of the surrounding walls and most of the wall paintings in the chancel and transepts. These frescoes were replaced during two years' restoration work, after which the church reopened on 24 February 2009 with a solemn mass presided over by Paolo Romeo, archbishop of Palermo, and attended by several Jesuits and civil and military officials.