Screening priority pollutants from vast anthropogenic contaminants discharged into aquatic environment is urgent for protecting water quality definitely. The multi-criteria scoring method involved in the occurrence (O), persistence (P), bioaccumulation (B), ecological risk (Eco-T), and human health risk (Hum-T), was established for pollutants prioritization in waters and applied in Dongping Lake, the final impoundment reservoir along the eastern route of China's South-to-North Water Diversion Project (SNWDP). A total of 170 chemicals including heavy metals (HMs), volatile organic chemicals (VOCs), polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), phthalate esters (PAEs), and antibiotics (ANTs) were investigated as the candidates. Accordingly, 42 chemicals including 8 PAEs, 7 OCPs, 7 PCBs, 5 PAHs, 13 HMs, and 2 VOCs were made up the list of priority pollutants for Dongping Lake, suggesting the necessity of routine monitoring high priority groups and revising the existing list. Multiple risk assessment indicated higher ecological and human health risks induced by HMs than by organic pollutants. Spatial distribution of risks stressed the retention of toxic organic chemicals by the lake body and the accumulation of HMs along the transfer route, respectively, thus triggering ecosystem responses and potential effects on the water-receiving areas as expected.