It is assumed that the island, since ancient times, had an important strategic function to control the waterways towards the hinterland, which in Roman times went from Ravenna to Altino. Archaeological findings demonstrate the presence of man in the area since the Bronze Age, while the first official public act dates back to 1050 and calls the island "Vigna Murada".

The property of the island was, from the end of the eleventh century, of the Benedictine monks of San Giorgio Maggiore who erected a place of worship dedicated to San Bartolomeo; the island was surrounded by salt pans and the largest salt producer in the northern lagoon was the island of Torcello.

A decree of the Senate of the Serenissima sanctioned that, starting from 1468, the island of Vigna Murata carried out duties of Lazzaretto with the aim of preventing plague infections; the attribute "Novo" was assigned so as not to confuse it with the lazar called Vecchio, near the Lido, in which the plague patients were hospitalized. The ships, coming from the Mediterranean and suspected of being carriers of the epidemic, were quarantined on the island, providing it with an adequate sanitary system and a series of cells (rooms) to accommodate people and large spaces covered by canopies to sanitize the goods through the use of aromatic herbs.

The Tezon Grande, the heart of the island as well as one of the largest public buildings in Venice, has a length of 100 meters and preserves an unparalleled patrimony of writings and drawings that attest to the trade and the health and merchant activities that were carried out on the sole, as well as a system of certification of goods through seals and symbols.

The intended use of the building for sanitary purposes changed during the 1700s when, under Napoleonic and then Austrian rule, it became a piece of the lagoon's efficient defensive system: the Tezon arches were closed to become a powder keg and also the city walls it was fortified accordingly. It was connected with the Torre Massimiliana di Sant'Erasmo becoming the control point of the entrances to the Lido harbor.

The use of the island for defensive and military purposes declined in 1975 becoming an island abandoned and bound by the Ministry for Cultural Heritage and Activities. For some years, entrusted in concession to the Ekos Club association and bound by the Ministry for Cultural Heritage and Activities, the island has experienced a lively recovery activity, with important works by the Superintendence for Environmental and Architectural Heritage and the Water magistrate. The Ekos Club association made up of volunteers takes care, within the project "For the rebirth of an island", in collaboration with other bodies and institutions, of the management and custody of the island of Lazzaretto Nuovo, also takes care of the guided tours, which can be carried out from April to October, on Saturdays and Sundays at fixed times (at 9.45 am or 4.30 pm) or by reservation.

Since 1988, the Archeoclub association of Venice, in collaboration with the Superintendency of Archaeological Heritage of Veneto, the Universities of Venice and Padua, the International Center for Archaeological Research - CIRA, the French Rempart association and the European Forum of Heritage Associations, organizes archaeological fields in which adults, students and children can carry out work, restoration and maintenance camps, training courses and theoretical-practical internships to approach the world of archeology in a completely unusual way. During these camps, participants are hosted in the accommodation facilities present on site.

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