Worldwide, large investments in wastewater treatment are made to improve water quality. However, the impacts of these investments on river water quality are often not quantified. To assess water quality, the European Water Framework Directive (WFD) requires an integrated approach. The aim of this study was to develop an integrated ecological modelling framework for the River Drava (Croatia) that includes physical-chemical and hydromorphological characteristics as well as the ecological river water quality status. The developed submodels and the integrated model showed accurate predictions when comparing the modelled results to the observations. Dissolved oxygen and nitrogen concentrations (ammonium and organic nitrogen) were the most important variables in determining the ecological water quality (EWQ). The result of three potential investment scenarios of the wastewater treatment infrastructure in the city of Varaždin on the EWQ of the River Drava was assessed. From this scenario-based analysis, it was concluded that upgrading the existing wastewater treatment plant with nitrogen and phosphorus removal will be insufficient to reach a good EWQ. Therefore, other point and diffuse pollution sources in the area should also be monitored and remediated to meet the European WFD standards.