This study presents a basin-scale approach to the analysis of receiving water body quality considering both point and non-point pollution sources. In particular, this paper describes an extensive data gathering campaign carried out in the Nocella catchment, which is an agricultural and semi-urbanised basin located in Sicily, Italy. Two sewer systems, two wastewater treatment plants and a river reach were monitored during both dry and wet weather periods. A mathematical model of the entire integrated system was also created. Specifically, a detailed modelling approach was developed by employing three well known models: Storm Water Management Model, GPS-X and Soil and Water Assessment Tool. The study proposed a comprehensive modelling approach to analyse the importance of diffuse and concentrated polluting sources on receiving water quality. The study demonstrated that point pollution loads can be more influential during wet periods by an order of magnitude compared with the dry weather period. In the long term, diffuse and point pollution sources were demonstrated to affect river quality and they have both to be considered. The use of the proposed integrated model-based approach may support water managers in decision making about which strategies should be preferred with the aim of water quality preservation.