[1] The plot was located on the south bank of Arno in the sesto (one of the six sestieri of Florence) Oltrarno, within the communal walls of 1173–1175,[2] but in a sparsely populated area.

[4] The churches and convents of mendicant orders were constructed with the financial support of the commune, which provided funds for Santo Spirito in 1267,[5] and then from 1292 to 1301.

It also was involved in charity: friar Simone Fidati da Cascia directed the laudese foundation of a house for former prostitutes.

As the only area of the city located across the Arno, the sieste (from 1343 the quarter) of Santo Spirito was physically and politically apart from the rest of Florence.

[9] One of the most sensational political assassinations in the history of the Republic of Florence was a murder of Sandro da Quarata, a prominent member of the Ricci faction, in November 1370, when he was exiting the church after mass.

[10]: 199 In the lead up-to the Ciompi revolt the monastery was attacked by rioters on 22 June 1378, but defended by the forces loyal to the signoria.

During the sacra rappresentazione "Descent of the Holy Spirit" organized by the laudese in honor of the visit of Galeazzo Maria Sforza the old church caught fire and was heavily damaged, together with parts of the convent.

[11] After his death, the works were carried on by his followers Antonio Manetti, Giovanni da Gaiole, and Salvi d'Andrea; the latter was also responsible for the construction of the cupola.

In 1489, a columned vestibule and octagonal sacristy, designed by Simone del Pollaiolo, known as Il Cronaca, and Giuliano da Sangallo respectively, were built to the left of the building.

The most significant is the Bini-Capponi Chapel, housing the St. Monica Establishing the Rule of the Augustinian Nuns painting by Francesco Botticini.

The sacristy, accessed through a doorway in what would have been the left sixth chapel preceded by a monumental vestibule by Simone del Pollaiolo, was designed by Giuliano da Sangallo in 1489, and has an octagonal plan.

It is home to a devotional painting of St. Fiacre curing the Sick (1597) by Alessandro Allori (1596) commissioned by Christine of Lorraine, Grand Duke Ferdinando I de' Medici's wife.

The 38 chapels and their works of art are:[14] Michelangelo Buonarroti, when he was seventeen years old, was allowed to make anatomical studies on the corpses coming from the convent's hospital; in exchange, he sculpted a wooden crucifix which was placed over the high altar.

The former convent also contains the great refectory (Cenacolo di Santo Spirito) with a large fresco portraying the Crucifixion over a fragmentary Last Supper, both attributed to Andrea Orcagna (1360–1365).