The mobility of hunter-gatherer groups is crucial in understanding Palaeolithic settlement dynamics. The concept of mobility cannot be separated from the space in which it occurs, including landscape components, localization of critical resources and of other sites, and routes between them. Nevertheless, the landscape is not constant in time due to the geomorphological changes that occurred in the long timescale of Prehistory. Here we present a paleogeographic reconstruction of the coastal area around Grotta dei Santi during the Neandertal occupation. A GIS-based approach, combining geological, bathymetric, and sea-level fluctuations data, allows us to reconstruct the landscape around the cave at about 45 ky BP. The cave today opens onto a cliff facing the sea. The Neandertal occupation occurred with a sea-level 74 m lower than present-day. Consequently, the cave faced a vast coastal plain, playing a strategic role due to its position, allowing both proximity and control of essential resources.