Catchment-scale nitrate dynamics involve complex coupling of hydrological transport and biogeochemical transformations, imposing challenges for source control of diffuse pollution. The Damköhler number (Da) offers a dimensionless dual-lens concept that integrates the timescales of exposure and processing, but quantifying both timescales in heterogeneous catchments remains methodologically challenging. Here, we propose a novel spatio-temporal framework for catchment-scale quantification of Da based on the ecohydrological modeling platform EcH₂O-iso that coupled isotope-aided water age tracking and nitrate modeling. We examined Da variability of soil denitrification in the heterogeneous Selke catchment (456 km², central Germany). Results showed that warm-season soil denitrification was of catchment-wide significance (Da >1), while its high spatial variations were co-determined by varying exposure times and removal efficiencies (e.g., channel-connected lowland areas are hotspots). Moreover, Da seasonally shifted from processing-dominance to transport-dominance during the wet-spring season (from >1 to <1), implying important linkages between summer terrestrial denitrification and subsequent winter river water quality. Under the prolonged 2018–2019 droughts, denitrification removal generally reduced, resulting in further accumulation in agricultural soils. Moreover, the space-time responses of Da variability indicated important implications for catchment water quality. The older water in lowland areas exhibited extra risks of groundwater contamination, whilst agricultural areas in the hydrologically responsive uplands became sensitive hotspots for export and river water pollution. Importantly, the lowland pixels intersecting river channels exhibited high removal efficiencies, as well as high resilience to the disturbances (wet-spring Da shifted to >1 under drought conditions). The proposed catchment-wide Da framework is implied by mechanistic modeling, which is transferable across various environmental conditions. This could shed light on understanding of catchment N processes, and thus providing site-specific implications of non-point source pollution controls.