The aims of the study were to quantify nutrient loads from point and diffuse pollution sources in the Rio Mannu stream and to simulate mitigation measures for reducing nutrient loads delivered to the Santa Gilla wetland. The Soil and Water Assessment Tool model was used for simulating hydrology, nutrient balance and water quality. At the basin scale, the input from fertilisers was 80.3 kg ha−1 year−1 total nitrogen (TN) (87.6% of the total input) and 27.6 kg ha−1 year−1 of total phosphorus (TP) (99.8% of the total input). Atmospheric deposition and biological N-fixation together accounted for about 12% of the total TN input. The TN and TP from wastewater treatment plants (WWTPs) were about 14.2 t year−1 and 3.1 t year−1, respectively. Nutrient loads delivered to the river system differed among the sub-basins, with TP ranging from 0.2 kg ha−1 year−1 to 2.7 kg ha−1 year−1, and the sum of organic N and NO3-N ranging from 1.8 kg ha−1 year−1 to 22.9 kg ha−1 year−1. Under high flow conditions, NO3-N and TP accounted for 89% and 99% of the total load, respectively. The low flow contribution to the total load was very low, with NO3-N and TP accounting for 2.8% and 0.7%, respectively. However, the natural hydrological regime in the study area is intermittent, and low flow represents a critical condition for the water quality due to the high concentrations of TP and NO3-N from WWTP discharge. To improve the water quality, the reuse of treated wastewater from three WWTPs for irrigation purposes on olive cultivation, coupled with a 20% reduction in fertiliser application, was simulated. The results showed a reduction in nutrient loads at the outlet for all hydrological conditions. However, additional measures are needed for improving water quality.