Why have ecological targets for the majority of water bodies in Europe not been met despite decades of water protection programs? We hypothesize that restoration strategies have not adequately accounted for whole-river network perspectives, including interactions between stream orders, spatial patterns of pollutant sources, and ecoregion-dependent susceptibility. We used high-resolution data from Germany to identify relationships between urban wastewater-river discharge fraction (UDF), agricultural land use fraction (ALF), and ecological status by stream order across three ecoregions. Low-flow UDF values were used to reflect the strong vulnerability of low-order streams under these conditions. We found ecological status of good or better in less than 8% of all river sections with the highest proportions in low-order streams and complete disappearance at higher orders. Increasing ALF impaired the ecological status for river reaches across all stream orders. In contrast, relationships between UDF and ecological status impairment were significant only in low-order streams, independent from ecoregion. Concentrating integrative restoration efforts in low-order streams would maximize the potential to mitigate anthropogenic impacts.