Abstract: This study was designed to investigate the effect of minocycline on microglia activation of M1/M2 phenotypes. The model was induced by lipopolysaccharide (LPS) in BV-2 microglia cells, and was used to evaluate the effect and mechanism of minocycline. We measured nitric oxide (NO), prostaglandin E₂ (PGE₂), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) in M1 type microglia, and interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) in M2 type microglia through enzyme linked immunosorbent assay (ELISA). We used flow cytometry to detect the expression of M1 marker CD16/32 and M2 marker CD206 in order to evaluate the influence of minocycline on microglia activation of M1/M2 polarization. Finally, we explored the mechanism of minocycline through detection of the protein expression in response to activation of toll like receptor 4 (TLR4)-mediated myeloid differentiation factor 88 (MyD88) dependent pathway, mitogen activated protein kinase (MAPK) signaling and nuclear factor-κB (NF-κB). The results suggest that minocycline obviously inhibited the production of NO, PGE₂, TNF-α and IL-6, and increased the production of IL-10, TGF-β in LPS-stimulated BV-2 cells. Minocycline significantly down-regulated the expression of M1 marker CD16/32 and up-regulated the expression of M2 marker CD206. These results suggest that minocycline can inhibit the activation of microglia to M1 phenotype and promote the transformation of M2 phenotype through down-regulation of p38 and NF-κB signaling pathways.