Founded by a Franciscan missionary, Friar Joost de Rijcke, San Francisco complex construction began around 1550 and took almost 143 of construction through earthquakes and changes to its architectural style. In the early seventeenth century, and after a dramatic expansion, the Roman Catholic temple became the largest colonial temple ensemble among the historical structures of Latin America. San Francisco Church and its convent encompass three hectares including 13 cloisters, three churches, and a large courtyard. It is commonly named by historians as the "Escorial of the New World".

The San Francisco de Quito convent defined itself in its relations with the outside world according to three spaces: a public square built to integrate public activities as teaching, various markets, and water supply; a Courtyard where urban and some sacred functions met and accessed through the convex staircase, designed by the Vatican architect, Gian Lorenzo Bernini; and last the Church and its chapels. 

The façade of the church featured Mannerist elements for the first time in South America, It inspired other architects to apply this style to other catholic buildings. The building's Renaissance and Mannerist exterior contrasts with the inner decoration of the Church, in which Mudejar and Baroque elements bathe the nave, chapels, and high altar in an exotic golden splendor.

The San Francisco museum houses over 3,500 works of colonial art, of varied artistic styles and techniques, most notably those of the famous Quito School of art, which had its genesis precisely here. Undoubtedly the most celebrated of these is the 18th-century sculpture known as the Virgin of Quito, which has long been a kind of icon of the city. Here also is a magnificent Franciscan library, described in the 17th century as the best of the Viceroyalty of Peru.