The Water Framework Directive (WFD) of the European Union requires member states to achieve good ecological status of all waterbodies. A harmonized pan-European assessment of water resources availability and quality, as affected by various management options, is necessary for a successful implementation of European environmental legislation. In this context, we developed a methodology to predict surface water flow at the pan-European scale using available datasets. Among the hydrological models available, the Soil Water Assessment Tool (SWAT) was selected because its characteristics make it suitable for large scale applications with limited data requirements. This paper presents the results for the Danube pilot basin. The Danube Basin is one of the largest European watersheds covering ca. 803,000 km2 and portions of 14 countries. The modeling data used included land use and management information, a detailed soil parameters map, and high resolution climate data. The Danube Basin was divided into 4,663 subwatersheds of an average size of 179 km2. A modeling protocol is proposed to cope with the problems of hydrological regionalization from gauged to ungauged watersheds, and over-parameterization and identifiability, which are usually present during calibration. The protocol involves a cluster analysis for the determination of hydrological regions and multi-objective calibration using a combination of manual and automated calibration. The proposed protocol was successfully implemented, with the modeled discharges capturing well the overall hydrological behavior of the basin.