River basins are extremely complex hierarchical and directional systems that are affected by a multitude of interacting stressors. This complexity hampers effective management and conservation planning to be effectively implemented, especially under climate change. The objective of this work is to provide a wide scale approach to basin management by interpreting the effect of isolated and interacting factors in several biotic elements (fish, macroinvertebrates, phytobenthos and macrophytes). For that, a case study in the Sorraia basin (Central Portugal), a Mediterranean system mainly facing water scarcity and diffuse pollution problems, was chosen. To develop the proposed framework, a combination of process-based modelling to simulate hydrological and nutrient enrichment stressors and empirical modelling to relate these stressors - along with land use and natural background - with biotic indicators, was applied. Biotic indicators based on ecological quality ratios from WFD biomonitoring data were used as response variables. Temperature, river slope, % of agriculture in the upstream catchment and total N were the variables more frequently ranked as the most relevant. Both the two significant interactions found between single hydrological and nutrient enrichment stressors indicated antagonistic effects. This study demonstrates the potentialities of coupling process-based modelling with empirical modelling within a single framework, allowing relationships among different ecosystem states to be hierarchized, interpreted and predicted at multiple spatial and temporal scales. It also demonstrates how isolated and interacting stressors can have a different impact on biotic quality. When performing conservation or management plans, the stressor hierarchy should be considered as a way of prioritizing actions in a cost-effective perspective.