It was founded in 1929 with the name of Museo Provinciale di Storia Naturale di Livorno in order to house the scientific material of the Department of Natural History of the "Amerigo Vespucci" Technical Institute, collected from 1871 to 1909 by illustrious natural scientists of Livorno. Bombed in 1944, most of its holding was destroyed. Reopened to the public in 1952, in 1980 the Museum was transferred to its present location in the eighteenth-century Villa Henderson which houses offices, the library and several laboratories.

The Museum has an area mainly dedicated to cetaceans (Sea Room), a learning trail on human evolution in the Mediterranean area (Room of Man), other natural science sections, and a well-equipped area for scientific and environmental education.

The garden of the villa hosts a Botanical Garden dedicated to the flora of the Mediterranean regions, subdivided into sectors on the basis of the diverse substrata (calcareous, gabbroid rock, granites, dunes and wetlands). The botanical collections are enriched by herbaria of plant species from Tuscany and from the desert of Southern Jordan. A seed bank conserves elements from the territory of the province of Livorno and from the Botanical Garden.

Also noteworthy is the Planetarium that enables the virtual exploration of the sky, accompanied by the scientific personnel of the Museum and by experts of the Associazione Livornese Scienze Astronomiche (ALSA).