Pollen analysis was carried out on the infilling succession of the Fossa San Vito sinkhole, at the NE foothills of the Sarno Plain (Italy). Four 14C dates and six tephra layers constrain the pollen sequence between ca. 6000 and 500 cal yr BP. A forested environment, with a few signs of human activities, characterizes the pre-protohistoric period (ca. 6000–2750 yr BP). Stability of the arboreal pollen grains to non-arboreal pollen grains (AP/NAP) curve is due to climate-related opposite oscillations of deciduous and evergreen forest. In this period, the pyroclastic products from Neapolitan volcanoes that reached the upper Sarno Plain seem to have affected neither vegetation nor human activities. In the archaic and classic periods (ca. 2750–1500 yr BP), intensive deforestation and increase in anthropogenic indicators indicate the occurrence of grazing and crop activities managed by the main urban centers located in the plain: Pompeii, Stabiae, and Nuceria. After the Pompeii eruption in CE 79, a rapid re-afforestation and decline in all anthropogenic indicators testify to the temporary abandonment of the area, linked to the disastrous demise of the main economic centers. The upper plain was repopulated and exploited in the Late Ancient and Middle Ages (ca. 1700–500 yr BP), as indicated by the increase in all crop and grazing indicators.