Founded in 1862, the School is situated in the former monastery of the Augustinians, remodelled in 1820 by the architect Agostino Fantastici after it had been seriously damaged in a disastrous fire. Up to 1932 the institute had been named for Francesco Guicciardini, and only at a later time for Enea Silvio Piccolomini. Since 2000 it has been a part of the Istituto di Istruzione Superiore "Enea Silvio Piccolomini" ["Enea Silvio Piccolomini" Institute of Higher Education].

The School possesses a series of interesting naturalist collections, probably formed at the initiative of the individual professors of Natural Sciences in the 19th century and the early 20th, including over 300 fossil specimens, palaeo-anthropological specimens, minerals and rocks, marbles, zoological collections of birds, mammals, marine animals and insects, and botanical collections. The area of research, as can be seen from the labels, covers mainly the Sienese territory and southern Tuscany, without neglecting the Island of Elba, from which come numerous specimens. The collection also contains a herbarium of plants gathered starting from 1879 by the botanist Freda and now kept at the Accademia dei Fisiocritici in Siena.