Pharmaceutical pollution is escalating due to the increasing prevalence of diseases driven by an aging population and socioeconomic and hydroclimatic changes, challenging the EU’s goal of achieving a toxic-free environment. To comprehensively assess pharmaceutical pollution in rivers, we developed a spatially resolved model to predict pharmaceutical concentrations and associated ecological risks across 1 km river stretches in Saxony, Germany. We focused on five pharmaceuticals: two antiepileptics (carbamazepine, gabapentin), two antibiotics (ciprofloxacin, sulfamethoxazole), and one antidiabetic (metformin); and their toxicity to three aquatic species: algae, daphnia, and fish. Model evaluation demonstrated a good level of accuracy, with 95–100% of simulations aligning within 1 order of magnitude of observed values across spatial and temporal scales (2008–2014). Pharmaceutical-wise, low environmental concentrations led to a reduced performance of ciprofloxacin, whereas frequent observations of carbamazepine demonstrated its improved model skill. Further, ecological risk assessments for single toxicity indicated significant risks in over half of the Saxon rivers, with exposure frequencies reaching up to 80% for the analyzed pharmaceuticals. For mixture toxicity, the risk frequency increased to 99%, revealing widespread ecotoxicological risks. Our framework identifies transport trajectories and risk hotspots of pharmaceutical pollution, enabling spatiotemporal predictions under global change conditions to support proactive measures for a healthier planet.