Polycyclic aromatic hydrocarbons (PAHs) in water are readily adsorbed onto microplastics, posing a combined threat to aquatic ecosystem safety. However, the role of microplastics in altering the toxicity of PAH derivatives remains largely unexplored. This study was conducted to investigate the individual and combined toxic effects of polystyrene (PS, 2 µm) microplastics with pyrene (Pyr) and its four derivatives, including 1-methylpyrene (Pyr–CH₃), 1-hydroxypyrene (Pyr–OH), 1-aminopyrene (Pyr–NH₂), and 1-pyrenecarboxylic acid (Pyr–COOH), on blue mussels (Mytilus edulis). After a seven-day exposure experiment, the variations in five biomarkers—superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), malondialdehyde (MDA), and acetylcholinesterase (AChE)—were measured in the hemolymph. Our results indicated a com-pound-specific toxicological profile: all derivatives exhibited higher toxicity than the parent Pyr. Specifically, Pyr–CH₃ primarily induced oxidative stress, whereas Pyr–OH, Pyr–NH₂, and Pyr–COOH mainly affected neuroregulatory function. More importantly, PS microplastics acted as a differential modulator under the mixture conditions: they exacerbated the neuroregulatory dis-turbance caused by parent Pyr but conversely alleviated the oxidative damage induced by all four derivatives. Notably, PS exacerbated the neuroregulatory disturbance induced by Pyr–CH₃. These compound-specific interactions highlight that microplastics alter the toxic effects of organic pollutants, thereby modifying environmental risk profiles. Our findings provide new insights for the ecological risk assessment of PAHs in aquatic environments.