Agricultural land use poses a significant threat to the ecological integrity of rivers in Europe. Particularly in the Mediterranean, water abstraction and nutrient application are anthropogenic pressures that have a significant impact on aquatic habitats and biodiversity. In this article, we assessed the effects of agricultural management practices on benthic macroinvertebrates in a large river basin of central Greece using simulated data based on the application of SWAT (Soil Water Assessment Tool) model. Physicochemical and hydrological output variables of the model were used as predictors of the ASPT (Average Score Per Taxon) metric based on a correlated component regression analysis (CCR) built on empirical data. The estimation of ASPT was performed for the wet and dry seasons within a 20-year period for a total of 47 subbasins under the baseline conditions and after implementing three management scenarios that reduced: a) irrigation water applied to crops by 30%, b) chemical fertilization applied to crops by 30% and c) both irrigation and fertilization by 30%. The results revealed that application of the reduced irrigation resulted to a slight increase of the simulated dissolved inorganic nitrogen concentration (DIN), which in turn decreased the mean ASPT in 21 of the 47 subbasins implying a negative effect on the macroinvertebrate communities. On the contrary, the reduction of fertilization as well as the combined scenario decreased both the simulated DIN and phosphate concentration causing an increase of the mean ASPT for a total of 40 of the 47 subbasins. Based on these results, we suggest that the best management option is a combined practice of deficit irrigation and fertilization reduction since it improved water quality, increased ASPT values and saved a considerable amount of water. Overall, this work demonstrates a simple methodology that can efficiently assess the effects of agricultural management practices on biotic indicators.