AbstractNanoplastics (NPs) has become a worrying serious environmental problem. However, the toxicological effects and mechanisms of NPs on hematopoiesis are still unknown. To this end, male C57BL/6J mice were directly exposed to the serial concentration gradient of polystyrene NPs (PSNPs, 0, 30, 60, and 120 μg d), respectively, for 42 days by intragastric administration. Results show that PSNPs were clearly visible in bone tissues, meanwhile, induced the count of major blood indicators (WBC, RBC, and LYM) decreased. H&E staining displayed that exposed to PSNPs can cause hematopoietic damage of BM and extramedullary hematopoiesis in spleen. Flow cytometry result show that the proportion of LSK represented a dose‐dependent significantly decreased after PSNPs exposure. Further research found that PSNPs can cause the systemic oxidative stress occurs manifested as MDA accumulated. In addition, as the dose of PSNPs increased, the fluorescence intensity of Keap1 and p53 in femur sections gradually increased, meanwhile, the expression of cell oxeiptosis signal pathway Keap1/PGAM5/AIFM1 and the cell senescence signal pathway p53/p21 was all increased, markedly. Overall, our study demonstrated that PSNPs exposure caused oxidative stress, potentially resulting in cell oxeiptosis and senescence to develop haematotoxicity in C57BL/6J mice.