This paper is a case study about a natural catastrophic event that caused a human disaster in the medieval Benedictine enclave of Santa Maria in Portonovo—a large landslide involving some 5 million cubic meters of rock, which suddenly collapsed from the northeastern flank of the Monte Conero anticline hurling down from 400 m elevation over the littoral zone of the Portonovo bay, ∼9 km south of the Adriatic port city of Ancona. This landslide is the largest of the Conero Riviera, a 16-km-long, seismically active high coast with cliffs overhanging directly over the sea, which is therefore particularly prone to landsliding. While the landslide risk along the Conero Riviera has been evaluated by the local municipal authority, the risk in the Portonovo bay, a very popular beach resort, has been somewhat underestimated inasmuch as the huge landslide was previously considered, by geologists and geoengineers, to be a prehistoric event and therefore unimportant in the context of prevention plans aimed at assessing the hydrogeological instability of this area. We approached our study by surveying the area of the landslide using detailed ground truthing and geological mapping, and defining the geomorphology and lithologic composition of the landslide from head to toe. Radiocarbon dating of neritic mollusk shells from the autochthonous sediments underlying the landslide toe, which were retrieved from two drill cores from the toe of the landslide deposit, indicated that the landslide occurred in historical times, contrary to common belief that it occurred in prehistory. We then reconstructed the history of environmental changes of the Portonovo bay prior to, and subsequent to the landslide event using a detailed facies analysis of these two drill cores and of a third one drilled through the center of the landslide body. Written documentation about the medieval history of Portonovo, including an old map of the northeastern face of Monte Conero, which shows no evidence for the landslide, suggests that it occurred in the early fourteenth century, destroyed the strategic harbor of Novo Porto, and caused the definitive abandonment of the three-centuries-old Benedictine abbey of Santa Maria in A.D. 1320. The lithologic, structural, and rheologic setting of the steep northeastern flank of the Monte Conero anticline provided the predisposition for the huge medieval landslide, a structural setting possibly weakened by unusually intense seismic activity that affected the Conero Riviera from the late thirteenth to the early fourteenth centuries. The same structural and lithologic settings are found today on the slopes adjacent to the western side of the medieval detachment scar, thus representing a serious threat for the stability of the area and a high risk for imminent large landsliding, which may have grave consequences for present-day infrastructure and inhabitants of the popular Portonovo beach resort. Therefore, we present this work on the giant Portonovo landslide as an example of how interdisciplinary scientific investigation on hydrogeologically unstable areas may help in preventing human disasters.