Objective To investigate the regulatory role of nuclear factor erythroid 2-related factor 2 (Nrf2) in the activation and polarization of microglia induced by methamphetamine (METH). Methods BV2 and HMC3 cells were studied in vitro and wild-type mice and Nrf2-knockout mice were studied in vivo. In vivo and in vitro toxicity models induced by METH were established, respectively. The activation and polarization of microglia in each group were examined using immunofluorescence and Western blot, respectively. Results METH treatment significantly increased the fluorescence level of inducible nitric oxide synthase (iNOS) in BV2 and HMC3 cells (P<0.001), and significantly decreased the fluorescence level of Arginase1 (Arg1) (P<0.05, P<0.01). METH exposure activated microglia in the cortex, increased expression levels of ionized calcium binding adaptor molecule-1 (IBA1) and iNOS (P<0.001, P<0.05), and decreased the expression of Arg1 (P<0.01). The number of activated microglia was significantly increased after Nrf2 gene knockout (P<0.01), compared with the WT METH group, while the expression levels of IBA1 and iNOS were also increased (P<0.001, P<0.01) and the expression level of Arg1 was decreased (P<0.01). Conclusions Nrf2 plays an important role in regulating the activation and polarization of microglia induced by METH. Nrf2 may thus be a potential target for the treatment of neuroinflammation induced by METH.