The church was erected by the now-defunct religious order the "Humiliati" in the mid-14th century, under the direction of Tiberio da Parma, who is buried in the interior. It was initially dedicated to St. Christopher, patron saint of travellers, but its popular name suggesting consecration to Holy Virgin comes from the following century, when an allegedly miraculous statue of the Madonna, commissioned for the Church of S. Maria Formosa but rejected, was brought to the Church from the nearby orchard where it had languished.
The church lay on weak foundations and in 1399 a restoration project was financed by the city's Maggior Consiglio. The Humiliati, due to their "depraved customs", were ousted in 1462 and the Madonna dell'Orto was assigned to the congregation of Canons Regular of San Giorgio in Alga. The latter order was suppressed in 1668, and the following year the Church and convent annexed were handed over to Cistercians of Lombardy. In 1787 the church came under public administration. Restoration was begun under Austrian rule in the 1840s and finished in 1869, by which time Venice had become part of the unified Kingdom of Italy.
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