According to tradition, the Ospedale was founded in 1277 by the company of Santa Maria or "del Ceppo dei poveri" ("The offering trunk of the poor").

The current complex is the result of a series of additions and restorations of the original 13th-century edifice, which corresponds to today's corsia di Sant'Atto, a large ward with big windows now existing in a 16th-century renovation.

In the 15th century the wing and the current façade were added, with the Renaissance arcaded loggia built in 1502, inspired by the Ospedale degli Innocenti at Florence.

The loggia is decorated by a ceramic glaze frieze executed from 1525 by Santi Buglioni: it portrays the seven works of mercy, mixed with scenes of the Virtues.

The corsia di San Leopoldo ("Ward of St. Leopold"), now the seat of the Pistoia Medical Academy, was originally intended for the contagious patients.