Founded by the lay order of the Umiliati, the church was dedicated to all the saints and martyrs, known and unknown.

It is the burial place of the famous Early Renaissance painter, Sandro Botticelli, as well as Age of Discovery-era explorer Amerigo Vespucci, from whom the name "America" is derived.

Soon after, a new façade (1637) was erected using designs by Matteo Nigetti,[n 2] that conserved the glazed terracotta lunette over the doorway, which while resembling the work of Della Robbia, is now attributed to Benedetto Buglioni.

In the early 17th-century, the interior was remodeled in Baroque style, with the apse rebuilt with a pietre dure high altar[n 5] and a sotto in su perspective painting (1770) on the vaulted nave ceiling.

When Amerigo found a bay in the actual Brazil, he named to "San Salvatore di Ognissanti", in Portuguese "San Salvador de Todos os Santos": this is the origin of the name of the city of Salvador and Bahia de Todos os Santos.