The Istituto degli Innocenti was founded in the 15th century to care for abandoned children. Thanks to a bequest by Francesco Datini, a merchant from Prato, to which the funds of other merchants were added, its construction began in 1419 under the patronage of the Arte della seta (Silk Guild) of Por Santa Maria and was entrusted to Filippo Brunelleschi. Like every other reception centre of the time, it took Ospedale (Hospital) as its name.

In 1445, the Ospedale Santa Maria degli Innocenti began to care for children who were abandoned.

From the very beginning, the Ospedale enjoyed privileges, donations and bequests as well as the assets of other organisations. Until the suppression of the Guilds (1770), it was managed by the Council of Workers, appointed by the Silk Guild. It was then placed under the control of the Grand Ducal Government until the Unification of Italy, except for the period of the French domination (1799-1814) when it was managed together with other hospitals.

In 1862 it became an Opera pia and from 1888 was managed by a Board of Directors. In 1890, with the Crispi Law, it became a public charitable institution, and in 1923, an IPAB - Istituto pubblico per l'assistenza e la beneficenza (Institute for assistance and charity). Since 1940 it has been called Istituto, and in 2004 it became an ASP (Azienda di servizi alla persona - Company providing Care Services). The social and legal transformations that revolutionised Italy from the 1970s onwards also affected the functions of the Institute. Abandoned children decreased in number as did the number of mothers: the Institute's role changed from providing care and assistance to promoting initiatives to improve the living conditions of children and adolescents. The Institute became aware of new needs and started to collaborate with the Italian government, international institutions, bodies and associations that support children, young people and families. In 2004 the Institute became an ASP (Company providing Care Services).