The hospital was commissioned in 1419 by the Arte della Seta, the Florentine silk guild, which assumed responsibility for the care of abandoned children. Filippo Brunelleschi designed the building and oversaw construction during its first phase, between 1419 and 1427. Work continued under other masters after his departure, and the institution formally opened on 25 January 1445. The loggia facing the piazza — nine equal bays carried on slender Corinthian columns, with shallow pendentive vaults overhead — became the most studied element of the project, and one of the earliest applications of the classical orders to a wholly new civic typology.

Andrea della Robbia added the celebrated glazed terracotta medallions in the spandrels around 1490, replacing the blank concavities Brunelleschi had originally intended. Each tondo shows an infant in swaddling clothes against a deep blue ground, an emblem so closely identified with the institution that the American Academy of Pediatrics adopted a version of it as its insignia. Beyond the loggia, the building extended into a sequence of cloisters and wards organised around the Cortile degli Uomini and the Cortile delle Donne, separating the spaces for boys and girls and following a clear, repeatable geometry that would become a Renaissance standard for institutional architecture.

The hospital received foundlings until 1875. Since 1988 the building has also housed the UNICEF Innocenti Research Centre, and in 2016 the Museo degli Innocenti opened across three levels, presenting the institution’s history together with paintings by Domenico Ghirlandaio, Sandro Botticelli, Piero di Cosimo and members of the Della Robbia workshop. The Istituto degli Innocenti continues to operate from the same complex, six centuries after its foundation.