Meng and Yu Equal contributes. A B S T R A C TMicroglia inflammation induces pro-inflammatory cytokines and pro-inflammatory enzymes expression, thus leading to inflammation-mediated neuronal cell death. Increased intracellular glycolysis participates in LPS-mediated microglia inflammation. Dexmedetomidine exhibits neuroprotective effects in some situations. In this study, we mainly focused on whether and how dexmedetomidine inhibits LPS-mediated cellular glycolysis and inflammation in BV2 cells. LPS induced pro-inflammatory cytokines and pro-inflammatory enzymes expression, and increased glycolysis capacity in BV2 cells. Moreover, inhibition of glycolysis by 2DG attenuated LPS-induced pro-inflammatory cytokines and pro-inflammatory enzymes expression. Moreover, LPS upregulated hypoxia-inducible factor 1a (HIF1a) expression and decreased sirt1 expression. Dexmedetomidine counteracted these effects induced by LPS. Further, 2-methoxyestradiol, a HIF1a inhibitor, could inhibit LPSmediated glycolysis and inflammation in BV2 cells, which was similar to the effects of dexmedetomidine. In addition, these effects of dexmedetomidine could be reversed by EX527, a sirt1 inhibitor. The present study indicated that dexmedetomidine, via upregulation of sirt1 expression, inhibited HIF-1a expression and glycolysis, thus reducing LPS-mediated inflammation in BV2 cells.