[2] Soon after the founding of the city of San Francisco de Quito (6 December 1534), the entire southern side of the future Plaza Grande was given over to the Church.

The first temporary building, raised in the same year by Father Juan Rodriguez — first pastor of the fledgling town — was of adobe with wood frame and thatch roof.

[3][4] With the establishment of a parish of Quito (January 1545), a Bishop — García Díaz Arias — was named and reached the city on April 13 of the following year, along with Vicar General Pedro Rodríguez de Aguayo and plans to build a more eminent edifice.

[1] From 1562 to 1565, the building rose from its limestone foundations under the leadership of now Archdeacon Rodríguez de Aguayo, who served as acting bishop — Diaz Arias having died.

The anomaly of the main entrance not fronting onto the Plaza is explained by the presence of a deep gorge (la quebrada de Sanguña or Zanguña) present at the time of construction, which precluded extending the building backwards (toward the southwest).

After the eruption of Mount Pichincha, a local volcano which struck Quito in 1660, the damaged Cathedral was rebuilt by order of Bishop Alfonso de la Peña y Montenegro.

The small altar of Nuestra Señora de los Dolores (English: "Our Lady of Sorrows") has a plaque showing where President Gabriel García Moreno was shot in 1875.

The murder of the Bishop of Quito, José Ignacio Checa y Barba, took place here during the mass of Good Friday, 30 March 1877, when he was poisoned with strychnine dissolved in the consecrated wine.

Built on a plan comprising three longitudinal naves surmounted by semi-ogival arches on square pillars, the basic spatial structure of the cathedral is typical of the 16th century.

Based upon interior features — especially the details of the pillars, arches, and the carved and coffered ceiling — some experts assert that the cathedral should be characterized as Gothic-Mudéjar in style.

Plaques on the exterior walls of the Cathedral commemorate the fourth centenary (1934) of the founding of the city: first, the site is celebrated as the launching point of the Amazon expedition of Francisco de Orellana (1511–1546).

Here also is a large wooden carved door, in a semi-circular arch, leading to La Iglesia de El Sagrario [Church of the Sanctuary], a 17th-century chapel attached to the main building[13] which is usually locked.

[1] On the Wednesday of Holy Week, a liturgy is held called "el Arrastre de Caudas", roughly "the dragging of the trains", said to be unique to this cathedral.

It derives from ancient Roman practice, in which a banner was passed over the body of a deceased general and then flown over his troops in a symbolic transfer of his qualities to them.

A second large cloth banner, black with a red cross, covers the altar and then is waved by the archbishop over the cathedral canons who have prostrated themselves after processing with their trains and then over the congregation.