Unlike most cathedrals in Spain, construction was not begun until the sixteenth century in 1518 in the centre of the old Muslim Medina, after acquisition of the Nasrid kingdom of Granada from its Muslim rulers in 1492. While its earliest plans had Gothic designs, such as are evident in the Royal Chapel of Granada by Enrique Egas, most of the church's construction occurred when the Spanish Renaissance style was supplanting the Gothic in Spanish architecture. Foundations for the church were laid by the Enrique Egas starting from 1518 to 1523 atop the site of the city's main mosque; by 1529, Egas was replaced by Diego de Siloé who worked for nearly four decades on the structure from ground to cornice, planning the triforium and five naves instead of the usual three. Most unusually, he created a circular capilla mayor (principal chapel) rather than a semicircular apse, perhaps inspired by Italian ideas for circular 'perfect buildings' (e.g., in Alberti's works). Within its structure the cathedral combines other of the Vitruvian orders of architecture.

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