The church of San Francesco della Vigna was built on a Latin cross plan with a wide central nave flanked by six (5+1) chapels on either side. The presbytery includes, in addition, two chapels on both sides (a major and a smaller one).

On the 26th of June 1253, Marco Ziani, a Venetian aristocrat, in his last will left to the Franciscan friars his vineyard with annexed houses and the little church located in St. Justine's quarter.

The Church and Friary were dedicated to St. Mark until the first half of 1300s; later they adopted St. Francis' name. The gothic Church, drawn by de' Barberi in his map of Venice, belongs to that period.

The Church was demolished in the first half of 1500s, and it was magnificently rebuilt. Many noble families chose to be buried in it and they embellished it with masterpieces of art and added artistic altars. Next to the first small Friary, which was a simple cloister close to the church, a new grand Friary was built in the 15th century, formed by three large cloisters.

The main one has arched columns all around, with one side facing the lagoon. Two smaller cloisters are connected to the front on the Church side. In 1810 the Friary was suppressed and became a navy barracks and later, under Austrian government, an artillery barracks. Many old and damaged rooms, useless to the barracks, were demolished; furthermore, in the big cloister, the northern columns were bricked up.

The Friary was bought back in 1881. Between 1953 and 1956 a drastic restoration took place: the external loggia was demolished, all the bricked columns were freed on two sides of the large cloister, all the salt-eaten walls were renovated, all the beams darkened by time were cleaned and other minor superstructures were demolished. In 1955, on the far west side, a new wing was added to be used as an information hall and as Provincial Curia (transferred in 2004 to Marghera's Friary). Since 1989, St. Bernardino Ecumenical Studies Institute, founded in Verona in 1981, has been located in St. Francesco della Vigna Friary.