Industrial and agricultural expansion has led to widespread release of emerging contaminants (ECs) into aquatic ecosystems, posing substantial risks to environment and human health. This study investigated the fate, ecological risk, and prioritization of phthalate esters (PAEs), per- and polyfluoroalkyl substances (PFAS), antibiotics, and pesticides in sediments of the Pengxi River in China’s Three Gorges Reservoir. Sediment samples from ten sites along the river’s upstream-downstream gradient were analyzed as follow: PAEs by GC-MS, and PFAS, antibiotics, and pesticides by LC-MS. Ecological risk was assessed using Risk Quotients (RQ) and a multidimensional Toxicological Prioritization Index (ToxPi) integrating persistence, bioaccumulation potential, (eco)toxicity, concentration, detection frequency, and experimental uncertainty. Total extractable concentrations spanned three orders of magnitude, with PAEs being the most prevalent (133–993 ng∙g⁻¹; mean: 466 ng·g⁻¹), substantially higher than antibiotics (4.32–12.4 ng∙g⁻¹; mean: 7.8 ng·g⁻¹), PFAS (0.37–1.41 ng∙g⁻¹; mean: 0.65 ng·g⁻¹), and pesticides (0.186–2.01 ng∙g⁻¹; mean: 0.47 ng·g⁻¹). ToxPi analysis identified PAEs as the highest-priority contaminants due to their elevated concentrations, persistence, and toxicity, followed by PFAS and antibiotics, whereas pesticides posed the lowest risk in this specific study. In contrast, the concentration-based RQ method, which relies solely on concentration and ecotoxicity, identified only a few PAEs and pesticides as medium-to-high risk. Consequently, the traditional RQ approach underestimated risks of PFAS and antibiotics. The study demonstrates ToxPi’s exceptional performance in integrating multifaceted data for evidence-based prioritization. These findings provide a scalable framework for risk assessment in other comparable riverine systems and offer actionable insights to guide regulatory strategies targeting PAEs and PFAS.