Tradition holds that the Church of St. Mary Major was founded by Pope Simplicius in the second half of the 5th century on territory belonging to an ancient Roman villa in Tivoli.
Thanks to Pope Eugene III, the church and the monastery annex were expanded in 1100. The church passed into various Orders over time, until it was entrusted to the care of the Conventual Franciscans in 1241. However, they only began to inhabit the monastery in 1256 after prompting from Pope Alexander IV. In 1461, it passed to the Franciscan Friars and took the name Church of St. Francis. This name, however, was never truly accepted by the population of Tivoli which was extremely attracted to the Marian tradition and the building's previous dedication to St. Mary Major or 'Our Lady'.
In the mid 16th century, the Franciscan complex of church and convent was radically transformed by the building of the Villa d'Este. The monastery was partially demolished and the church façade moved to the side of the monastery, traces of which are still visible in the white marble frames of the original windows.
The bell tower was commissioned by the guardian Father Costanzo da Roma in 1590, as was the main altar.
The church façade is divided into two parts: the lower holds a large white marble portal with ogival arch, four narrow lancet windows and two oculi, while the upper part, on the second floor, which corresponds to the central nave, has a large rose window and ends in a triangular tympanum. There is a marble tabernacle in an ogival arch set with columns on a shelf above the portal.
Compared to the interior, the church exterior retains much of its medieval character, with alternating bands of brickwork and rectangles of sandstone.
The church and convent were transformed in the mid 16th century with the building of the Villa d'Este. The ancient convent was demolished as were the chapels on the right aisle. The decoration of the Chapel of St. Francis and the new main altar also date to the mid 16th century.
In the centuries that followed, various decorative elements were added, including the paintings in the tondi of the nave and the vault of the apse by Michelangelo Cianti in 1883 and the insertion of many funeral inscriptions or commemorations.
In its present state, the church has a nave and two aisles, preceded by a wide transversal narthex which is joined to the nave by a large stone arch with twisted and ogival columns. The nave is separated from the aisles with narrow arches and quadrangular pillars, the ceiling is barrel vaulted with lowered round arches. There are fourteen tondi, seven on each side, containing portaits of the Franciscan saints, on the upper wall, below the string-course.
The spacious bema, which leads into the retro-choir, has a groin vault ceiling with a polychrome marble altar at the centre. The side aisles are different sizes, the left being rather narrow with three side chapels leading off it, while the right is wider, with no chapels and leads to the rooms of the sacresty. There are still large areas of Cosmateque mosaic preserved in the nave flooring.

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