Objective：This study aims to investigate the roles of Toll like receptor（TLR）-Pellino 1（Peli1） axis in methamphetamine（Meth）-mediated microglial inflammation and pathway in BV2 cells. Methods：Western blot was used to observe the expression of Toll like receptors（TLR），the downstream adaptor proteins of myeloid differentiation factor 88（MyD88）and TIR-domain-containing adaptor inducing interferon-β（TRIF）. In parallel，the expression of Peli1 protein was detected by Western blot. The downstream inflammatory factors and signal pathway regulated by Peli1 were observed by ELISA，real-time PCR and Western blot. Results：The expression of TLR3，TLR4，TLR7，TLR8 and TLR11 was significantly up-regulated after Meth treatment in BV2 cells. Meanwhile，the expression of MyD88 and TRIF was significantly increased，and TRIF level exhibited a concentration-dependent effect. Meanwhile，Meth obviously induced the expression of ubiquitin protein Peli1. Noteworthily，after Peli1 was down-regulated by RNA interference，the expression of inflammatory factors including inducible nitric oxide synthase（iNOS），tumor necrosis factor（TNF）-α and interleukin（IL）-6 were dramatically decreased，accompanied by the significant attenuation of nuclear factor（NF）-κB activation. Conclusion：The TLRs-mediated inflammatory signal plays an important role in the process of microglial inflammatory response induced by Meth. Therefore，the TLRs-Peli1 signal axis may be a promising target for the intervention of Meth neurotoxicity，which displays significant application.