T-LAK-cell-originated protein kinase (TOPK) is a newly identified member of the mitogen-activated protein kinase family. Our previous study has showed that TOPK has neuroprotective effects against cerebral ischemia-reperfusion injury. Here, we investigated the involvement of TOPK in microglia/macrophage M1/M2 polarization and the underlying epigenetic mechanism. The expression profiles, colocalization and in vivo interaction of TOPK, M1/M2 surface markers, and HDAC1/HDAC2 were detected after middle cerebral artery occlusion models (MCAO). We demonstrated that TOPK, the M2 surface markers CD206 and Arg1, p-HDAC1, and p-HDAC2 showed a similar pattern of in vivo expression over time after MCAO. TOPK co-localized with CD206, p-HDAC1, and p-HDAC2 positive cells, and was shown to bind to HDAC1 and HDAC2. In vitro study showed that TOPK overexpression in BV2 cells up-regulated CD206 and Arg1, and promoted the phosphorylation of HDAC1 and HDAC2. In addition, TOPK overexpression also prevented LPS plus IFN-gamma-induced M1 transformation through reducing release of inflammatory factor of M1 phenotype TNF-alpha, IL-6 and IL-1 beta, and increasing TGF-beta release and the mRNA levels of TGF-beta and SOCS3, cytokine of M2 phenotype and its regulator. Moreover, the increased TNF-alpha induced by TOPK siRNA could be reversed by HDAC1/HDAC2 inhibitor, FK228. TOPK overexpression increased M2 marker expression in vivo concomitant with the amelioration of cerebral injury, neurological functions deficits, whereas TOPK silencing had the opposite effects, which were completely reversed by the FK228 and partially by the SAHA. These findings suggest that TOPK positively regulates microglia/macrophage M2 polarization by inhibiting HDAC1/HDAC2 activity, which may contribute to its neuroprotective effects against cerebral ischemia-eperfusion injury.