Following the tradition of the Spanish cities reconquered from Islam, Ferdinand and Isabella ordered the Cathedral to be built on the site of the Great Mosque of Muslim Granada. At first it was to conform to the type of Gothic church inspired by the model of Toledo Cathedral, and it was to adjoin the Royal Chapel, a funerary edifice destined to hold the Royal Mausoleum, whose situation determined the plan of the Cathedral. Designed by the Gothic master Enrique Egas, only the polygonal wall of the east end had risen above the foundations when construction was interrupted until 1528. It was resumed in that year, now under the reign of Charles V, with a new project and a new classical Renaissance style under the direction of Diego de Siloé, trained in Italy.

Until his death in 1563, Siloé transformed the Gothic east end into a classical interior by constructing a circular space that evokes both the Pantheon in Rome and the Holy Sepulchre in Jerusalem. Both references are highly significant, since it was apparently intended at one point by Charles V to become a Royal Pantheon (i.e. mausoleum), and also because it may have symbolised the Christian triumph over the infidel in the West, as represented by the eucharistic monstrance beneath the baldachin shown in a print engraved upon the completion of the circular High Chapel. Another very significant feature designed by Siloé is the Portal of Forgiveness on the exterior of the transept.

The body of the Cathedral, on a basilica plan with five aisles, was finished two centuries later, and established a type of construction that was followed in the new cathedrals built in neighbouring parts of Andalusia and in America.