Objective To investigate the regulation of Nrf2 on activation and polarization of microglia induced by METH. Methods BV2 cells and HMC3 cells were studied in vitro. Wild-type mice and Nrf2 knockout mice were studied in vivo.TheStoxicity models induced by METH inSvivoSand inSvitro were established respectively. And the IF and WesternBlot were used to detect the activation and polarization of microglia in each group, respectively. Results After treatment with METH, the fluorescence level of iNOS(Marker protein of polarized M1 phenotype in microglia) increased significantly in BV2 and HMC3 cells, while the fluorescence level of Arg1 (Marker protein of polarized M2 phenotype in microglia) decreased significantly. The results showed that METH could induce microglia polarization, and enhance the pro-inflammatory effect, and reduce the anti-inflammatory effect of microglia. The Nrf2 gene knockout mice were used to further explore the regulation of Nrf2 on the activation and polarization of microglia induced by METH. The results showed that after exposure to METH, microglia in the cortex of mice were obviously activated, and the expression levels of IBA1 and iNOS were obviously increased, while the expression level of Arg1 was decreased. Compared with wild-type METH group, the number of microglia activated after Nrf2 gene knockout was significantly increased, while the expression levels of IBA1 and iNOS were increased and the expression level of Arg1 was decreased. The above results indicated that METH could enhance the pro-inflammatory effect of microglia and reduce its anti-inflammatory effect while inducing the activation and polarization of microglia. However, after Nrf2 gene was knocked out, the effect of METH activated microglia and its pro-inflammatory and anti-inflammatory effects were stronger. Conclusions Nrf2 plays an important role in regulating the activation and polarization of microglia induced by METH, and Nrf2 was expected to be a potential target for the treatment of neuroinflammation induced by METH.