Aquatic organisms in the environment are frequently exposed to a variety of organic chemicals, while these biological species may show different sensitivities to different chemical groups present in the environment. This study evaluated species sensitivity, hazards, and risks of six classes of organic chemicals in the aquatic environment. None of the taxonomic groups were the most sensitive or tolerant to all chemicals, as one group sensitive to one class of chemicals might possess adaptations to other chemical groups. Polychlorinated biphenyls were generally the most toxic chemical group, followed by polybrominated diphenyl ethers, polycyclic aromatic hydrocarbons, and pharmaceuticals and personal care products, while per- and polyfluoroalkyl substances and phthalate esters were the less toxic chemical groups. The hazard of organic chemicals was closely related to their physicochemical properties, including hydrophobicity and molecular weight. It was shown that 20% of the evaluated chemicals exhibited medium or high ecological risks with the worst-case scenario in the Pearl River Estuary. This novel work represented a comprehensive comparison of chemical hazards and species sensitivity among different classes of organic chemicals, and the reported results herein have provided scientific evidence for ecological risk assessment and water quality management to protect aquatic ecosystems against organic chemicals.