Anthropogenic activities, such as waste water treatment plants (WWTPs) discharges, impact the natural river regime. The assessment of the “impacted” and “un-impacted” hydrological conditions is of paramount importance for river management. Methodologies for characterizing flow regimes and their alterations are based on streamflow data recorded over a long period. Data requirements may be a limitation in regions where the recorded data are not available or poor (i.e. short time series, presence of gaps). Hydrological models, such as the Soil and Water Assessment Tool (SWAT), may be used to generate long-term time series of daily or monthly streamflow. This work defines an approach to characterize the flow regime of an intermittent river and assess its alterations using the SWAT model. The aims were: (i) calibrate SWAT for simulating daily streamflow in the Canale d’Aiedda river (Italy), (ii) characterize its flow regime, and (iii) assess the hydrological regime alterations due to WWTPs. The flow regime was characterized using several hydrological indicators, based on the long-term time series of modeled daily streamflow. The hydrological regime of river reaches receiving effluent from WWTPs shifted from intermittent to perennial. Low-flow metrics, including 1-, 3-, 7-, 30-, and 90-day minimum flows, and the occurrence of zero-flow days, were significantly altered. Additionally, monthly flow patterns during the summer period exhibited marked changes. The concept of “zero-flow threshold”, defined on field observations was introduced to improve the model results. This study provides a contribution to the significant topic of the management of intermittent rivers under the Mediterranean climate.