Nanoplastics (NPs), a growing environmental concern, can act as carriers for co-pollutants like bisphenol A (BPA). Consequently, understanding the combined toxicity of these pollutants is critical, as mammals are often exposed to multiple environmental contaminants simultaneously, however, the potential adverse effects of NPs and/or BPA remain inadequately defined. Therefore, we conducted a six-week toxicity study in mice to evaluate the impacts of BPA, polystyrene nanoplastics (PS-NPs), and their combination. Our results demonstrated that simultaneous exposure to BPA and PS-NPs significantly worsened growth-related toxicity and induced renal damage compared to individual exposures or controls. Mechanistically, co-exposure to BPA and PS-NPs markedly elevated renal malondialdehyde concentrations while significantly reducing the activities of catalase, superoxide dismutase and glutathione peroxidase. This oxidative imbalance led to the dysregulation of the mitochondrial antioxidant system and disruption of ferroptosis kinetics via inhibition of the PI3K/AKT signaling pathway. In conclusion, this study demonstrated the significantly enhanced nephrotoxicity of co-exposure to PS-NPs and BPA in mice, providing crucial mechanistic insights into the toxicological interactions between NPs and endocrine disruptors in mammals. These findings highlight the potential health risks posed by multi-pollutant exposures in the real world.