A volcanic catastrophe even more devastating than the famous anno Domini 79 Pompeii eruption occurred during the Old Bronze Age at Vesuvius. The 3780-yr-B.P. Avellino plinian eruption produced an early violent pumice fallout and a late pyroclastic surge sequence that covered the volcano surroundings as far as 25 km away, burying land and villages. Here we present the reconstruction of this prehistoric catastrophe and its impact on the Bronze Age culture in Campania, drawn from an interdisciplinary volcanological and archaeoanthropological study. Evidence shows that a sudden, en masse evacuation of thousands of people occurred at the beginning of the eruption, before the last destructive plinian column collapse. Most of the fugitives likely survived, but the desertification of the total habitat due to the huge eruption size caused a social-demographic collapse and the abandonment of the entire area for centuries. Because an event of this scale is capable of devastating a broad territory that includes the present metropolitan district of Naples, it should be considered as a reference for the worst eruptive scenario at Vesuvius.