Environmental and health concerns surrounding per- and polyfluoroalkyl substances (PFAS) have garnered increasing attention in recent years. The persistence and high mobility of PFAS present significant challenges in understanding their fate and transport in the environment. To address these challenges and gain insights into the contamination status at large catchment scale, as part of the EU Horizon 2020-project, we further developed the regionalized emission model system “MoRE”, to make it capable of quantifying PFAS emissions via multiple pathways across the Upper Danube Basin(Germany, Austria, Czech Republic, Slovakia, Hungary).The model operates on an annual temporal scale from 2015 to 2021 and with a spatial resolution of 526 sub-catchments in the size of 354 ± 352 km2. General input data were sourced from a combination of open-access databases and local ministry records. Hydrological information was obtained using the Wflow model developed by Deltares, while PFAS concentrations were derived from a comprehensive database integrating data from a 1.5-year monitoring campaign conducted across various environmental compartments within the investigated catchment, as well as additional information from previous studies.The model accounts for multiple emission pathways, including point sources such as urban wastewater treatment plants and industrial dischargers, and diffuse pathways, such as atmospheric deposition, groundwater flow, surface runoff, and soil erosion. Validation of the model against observational data from multiple river monitoring stations demonstrated pleasing performance, particularly for perfluoroalkyl carboxylic acids (PFCAs). These results underscore the model’s effectiveness in predicting in-stream PFAS loads and concentrations. However, the underestimation of certain substances suggests the presence of unaccounted emission sources.Key findings reveal that diffuse pathways, especially those associated with inhabitants and legacy contaminated spots (e.g.former firefighting foam applications and municipal landfills), contribute substantially to overall PFAS inputs. Furthermore, point-source emissions from industrial facilities, especially a PFAS production site, significantly influence PFAS concentrations, particularly for 'replacement compounds' like ADONA and GenX.By identifying key contamination hotspots and evaluating potential risks in the context of proposed regulatory thresholds and scenario evaluations, this study provides helpful insights for the water management sector. The model can guide targeted monitoring, inform decision-making for remediation efforts, and support the development of more effective regulatory frameworks to mitigate PFAS pollution at regional and catchment scales.