Wastewater effluents from irrigation and the domestic and industrial sectors have serious impacts in deteriorating water quality in many rivers, particularly in areas under tidal influence. There is a need to develop an approach that considers the impact of human and natural causes of salinization. This study uses a multi-objective optimization–simulation model to investigate and describe the interactions of such impacts in the Shatt al-Arab River, Iraq. The developed model is able to reproduce the salinity distribution in the river given varying conditions. The salinity regime in the river varies according to different hydrological conditions and anthropogenic activities. Due to tidal effects, salinity caused by drainage water is seen to intrude further upstream into the river. The applied approach provides a way to obtain optimal solutions where both river salinity and deficit in water supply can be minimized. The approach is used for exploring the trade-off between these two objectives.