It has been well documented that methamphetamine induces microglial activation and death, however, the molecular mechanisms underlying this process remain poorly understood. In the present study, we demonstrated the involvement of sigma-1 receptor (σ-1R) in methamphetamine-mediated microglial apoptosis. Exposure of BV-2 cells to methamphetamine induces cell apoptosis through its cognate receptor σ-1R, followed by activation of the mitogen-activated protein kinases, phosphatidylinositol-3’ kinase/Akt as well as the downstream transcription factor p53 pathways. Blockage of σ-1R significantly inhibited the increased pro-apoptotic proteins such as Bax, Caspase-3 and Caspase-9 induced by methamphetamine. In conclusion, these findings underscore the critical role of σ-1R in microglial apoptosis induced by methamphetamine. Understanding the link between σ-1R and apoptosis will lead to development of therapeutic strategies targeting methamphetamine-mediated microglial death/dysfunction.