As early as the 15th century, the French community in Rome, which owned a small chapel and a hospital dedicated to Saint Louis, began building a new church, supported by the generosity of Henry II, Henry III, and Catherine de' Medici. In 1478, Sixtus IV authorized the construction of a new church consecrated to the Virgin Mary, Saint Denis, and King Louis IX of France, and granted the title of parish to all French people living in Rome.

Known primarily as San Luigi dei Francesi, construction began in 1518 and was completed in 1589 by Domenico Fontana based on a design by Giacomo della Porta.

The church, from an artistic perspective, is an exaltation of France through the representation of its saints and greatest historical figures. The façade features statues of the "glories" of France. French: Charlemagne, Saint Louis, Saint Clotilde, and Saint Joan of Valois. Inside, there are frescoes depicting the apotheoses of Saint Louis and Saint Denis, and the story of the life of Clovis.

The church houses absolute masterpieces of 17th-century art. In the second chapel of the right aisle are Domenichino's fresco depicting the life of Saint Cecilia, and on the altar is a copy of Raphael's Saint Cecilia by Guido Reni. The fifth chapel of the left aisle (the Contarelli Chapel) houses three absolute masterpieces by Caravaggio illustrating the life of Saint Matthew: The Martyrdom of Saint Matthew, Saint Matthew and the Angel, and The Calling of Saint Matthew.