This study analyses nautical harbour activities and their spatial distribution using a high-resolution method of wind-wave hindcasting, in order to identify the location of safe and sheltered anchorage areas. We apply this methodological approach to evaluate the ancient harbour of Carthago Nova from the Punic period to the Late Roman period (third century BC–fourth century AD). Literary sources have defined Carthago Nova (Cartagena, Spain) as the only natural harbour of Hispania and one of the best in the Mediterranean, with Escombreras Island as the main natural feature that protects the harbour. Due to the scarcity of archaeological evidence and the transformation the harbour has undergone over time, this study has been considered necessary and carried out in order to supersede the current general and anachronic observations of wind-wave effects. Through an interdisciplinary approach, we analyse one of the main factors that determines the safe anchorage of ships: coastal wind waves. The modelling and simulation of waves have been applied using the SWAN model, paleo-topographic reconstruction, and maritime archaeological data. By means of GIS spatial analysis, an Anchorage Safety Index has been established that computes data from paleo-bathymetry, wind, and simulated wave height. This high-resolution analysis allows us to assess in detail the impact of coastal and island topography on nautical activities inside ancient harbours.