To explore contaminant concerns as a result of anthropogenic disturbance of the river system, this study provided the first extensive investigation of the contamination profiles, possible driving factors, and ecological risks of 40 target compounds including pharmaceuticals and personal care products (PPCPs), neonicotinoid pesticides (NNIs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) in sediments of the whole Yangtze River (the world's third longest river). Among these target compounds, PPCPs were the dominant contaminants with a total concentration (∑15PPCPs) of 2.13–14.99 ng/g, followed by ∑7PCBs (<LOD-1.97 ng/g), ∑11NNIs (<LOD-1.18 ng/g), and ∑7PBDEs (<LOD-0.78 ng/g). The results suggested that contamination levels of these chemicals were largely due to the amount used, low affinity with sediments, and effective management practices. Microplastics and anthropogenic factors (i.e., GDP per capita, population density, and urbanization rate) contributed significantly to PPCPs contamination based on correlation analysis (p < 0.05). The risk assessment suggested that PBDE 99, PBDE 183, E3, PCB 153, and PCB 118 posed relatively high risks when compared with other compounds. Therefore, it is not only necessary to take effective measures to reduce the contamination of legacy POPs, but also to improve the management and treatment of emerging organic chemicals to deal with the threat of them in the Yangtze River Basin.