Objective To investigate the effect of rehmannia polysaccharide on the renal injury in offspring of pregnant mice with hyperthyroidism, and on regulating the signaling pathway of nuclear factor E₂-related factor (Nrf2)/heme oxygenase(HO-1)/Nod-like receptor protein 3 (NLRP3). Methods Fifty-six female kunming mice pregnant successfully were randomly divided into normal group (n=12), model group (n=12), positive control group (n=10), rehmannia polysaccharide low-dose group(n=11) and rehmannia polysaccharide high-dose group (n=11) to establish pregnancy with hyperthyroidism model. The positive control group was given methimazole 5 mg/kg intragastric administration, and the low and high dose groups were given rehmannia polysaccharide 20 and 40 mg/kg intragastric administration respectively, once a day, until delivery. The body weight of female mice was measured, and the contents of free triiodothyronine (FT₃), free thyroxine (FT₄) and thyroid stimulating hormone (TSH)in the serum were detected by ELISA. Kidney tissue of young mice was observed by HE staining. The contents of urea nitrogen(BUN) and creatinine (Cr) in the serum of the young mice were detected by automatic biochemical analyzer. Superoxide dismutase(SOD) activity, malondialdehyde (MDA) content, interleukin (IL)-1β and IL-18 content were detected by ELISA, and the relative expression levels of Nrf2, HO-1 and NLRP3 proteins were detected by Western blotting. Results HE staining showed that the renal tubules and glomerulus in model group were disorganized, the basement membrane thickened significantly, large number of red blood cells infiltrated, and endothelial cells were edema. Compared with model group, the kidney tissue lesion reduced obviously in positive control group and rehmannia polysaccharide low and high dose group. The body weight of mice was significantly lower in model group than that in normal group, while was significantly higher in positive control group and rehmannia polysaccharide low-dose and high-dose groups than that in model group with statistical significance (P<0.05). ELISA results showed that the contents of FT₃ and FT₄ were significantly higher in model group than that in normal group, while the TSH content was significantly lower in model group than that in normal group (P<0.05). The contents of FT₃ and FT₄ were lower, while TSH content was higher in positive control group and rehmannia polysaccharide low-dose and high-dose groups than those in model group with statistical significance(P<0.05). The contents of BUN and Cr were higher in offspring of model group than those in normal group, while were lower in positive control group and rehmannia polysaccharide low-dose and high-dose groups than those in model group with statistical significance (P<0.05). ELISA results showed that the contents of MDA, IL-1β and IL-18 were higher, while SOD activity was lower in offspring of model group than that in normal group. The contents of MDA, IL-1β and IL-18 were lower, while SOD activity was higher in positive control group, low-dose and high-dose rehmannia polysaccharide groups than those in model group with statistical significance (P<0.05). Western blotting showed that the expression levels of Nrf2 and HO-1 were lower and NLRP3 was higher in model group than those in normal group. The expression levels of Nrf2 and HO-1 were higher, while NLPR3 was lower in positive control group and rehmannia polysaccharide low-dose and high-dose groups than those in model group with statistical significance(P<0.05). Conclusion Rehmannia polysaccharide can improve the thyroid function of pregnant mice with hyperthyroidism and protect their offspring from kidney damage, and Nrf2/HO-1/NLRP3 pathway may play such a role.