The location of the church of Santa María in the centre of what was once the city of the Alhambra, next to some Arab baths between the Nasrid palaces and the town houses, denotes that there must have been a mosque there previously. Nevertheless, the discovery of an ancient inscription from the Visigothic period above the door of the sacristy adds credence to the tradition that a Christian religious building stood there before the Islamic invasion.

Although the current building dates from the late 16th and early 17th centuries, the space had been enclosed since the early 500s. Proof of this was the disagreement between Emperor Charles V and the Archbishop of Granada when the Renaissance palace was constructed, since if this had been built parallel to the Nasrid palaces in order to join onto them perfectly, it would have invaded part of the space of the church, something the archbishop was not prepared to tolerate. The imperial palace was therefore built obliquely to the Islamic palaces.

Apart from its architectural form and volume, the fact that the building was the parish church of all the citizens who lived inside the precinct of the Alhambra made it the most evident sign of the Christian Alhambra. Kept inside it were such venerated images as that of Our Lady of the Anguishes, the patroness of the city of Granada, which is carried in procession during Holy Week in one of Granada's most beautiful religious festivities.