This study deals with the flood-hazard assessment and mapping in the catchment of Megalo Rema (East Attica, Greece). Flood-hazard zones were identified utilizing Multi-Criteria Decision Analysis (MCDA) integrated with Geographic Information System (GIS). Five factors were considered as the most influential parameters for the water course when high storm-water runoff exceeds drainage system capacity and were taken into account. These factors include slope, elevation, distance from stream channels, geological formations in terms of their hydro-lithological behavior and land cover. To obtain the final weights for each factor, rules of the Analytic Hierarchy Process (AHP) were applied. The final flood-hazard assessment and mapping of the study area were produced through Weighted Linear Combination (WLC) procedures. The final map showed that approximately 26.3 km2, which corresponds to 22.7% of the total area of the catchment, belongs to the high flood risk zone, while approximately 25 km2, corresponding to ~15% of the catchment, is of very high flood risk. The highly and very highly prone to flooding areas are located mostly at the southern and western parts of the catchment. Furthermore, the areas on both sides of the channel along the lower reaches of the main stream are of high and very high risk. The highly and very highly prone to flooding areas are relatively low-lying, gently sloping and extensively urbanized, and host the densely populated settlements of Rafina-Pikermi, Penteli, Pallini, Peania, Spata, Glika Nera, Gerakas and Anthousa. The accuracy of the flood-hazard map was verified by correlating flood events of the last 30 years, the Hydrologic Engineering Center’s River Analysis System (HEC–RAS) simulation and quantitative geomorphological analysis with the flood-hazard level. The results of our approach provide decision makers with important information for land-use planning at a regional scale, determining safe and unsafe areas for urban development.