Water security in a river basin in Italy was assessed using a water footprint sustainability approach. The study found that pollution from human activities, such as agriculture and wastewater treatment plants, was the main factor affecting surface water quality. To improve water security, lower pollutant thresholds should be set for effluent from treatment plants, natural areas should be expanded to support biodiversity, and soil management strategies should be enhanced to retain more water and reduce nutrient runoff. The research shows that a water footprint sustainability assessment can help manage water resources and achieve water security in areas facing multiple human pressures.