There are hundreds of thousands metric tons of microplastics (MPs) present in aquatic environments . The MPs coexist with other pollutants in water bodies , such as pharmaceuticals, and may carry and transfer them into aquatic organisms , consequently causing unpredictable ecological risks. The purpose of the present study was to evaluate the effect of the presence of polystyrene microplastics (PS-MPs) on the distribution and bioaccumulation of roxithromycin (ROX) in freshwater fish red tilapia ( Oreochromis niloticus ) as well as their interactive biochemical effects in red tilapia . PS-MPs were found to enhance the bioaccumulation of ROX in fish tissues compared to ROX-alone exposure. In the treatment of PS-MPs (100 μg L −1 ) combined with ROX (50 μg L −1 ), the highest concentrations of ROX reached 39,672.9 ± 6311.4, 1767.9 ± 277.8, 2907.5 ± 225.0, and 4307.1 ± 186.5 μg kg −1 in gut, gills, brain , and liver, respectively. Furthermore, compared to the ROX alone, the neurotoxicity caused by ROX was alleviated due to the presence of MPs after 14 d of exposure. The activities of cytochrome P450 (CYP) enzymes [7-ethoxyresorufin O-deethylase (EROD) and 7-benzyloxy-4-trifluoromethyl-coumarin O -dibenzyloxylase (BFCOD)] in fish livers exposed to all co-exposure treatments exhibited great variability compared to ROX alone after 14 d of exposure, suggesting that the presence of MPs may affect the metabolism of ROX in tilapia . Compared with ROX alone, the superoxide dismutase (SOD) activity increased significantly, and malondialdehyde (MDA) contents decreased in the co-exposure treatments, showing that oxidative damage in situations of co-exposure to MPs and ROX was mitigated in fish livers after 14 d of exposure. Collectively, the presence of MPs could affect the fate and toxicity of other organic pollutants in fish. The results emphasize the importance to study the interactions between MPs and other organic pollutants in aquatic environments.