Objective To evaluate whether dihydrotanshinone I (DHTS1) attenuates cuprizone-induced demyelination. Methods DHTS1 was dissolved in 5 g/L sodium carboxymethyl cellulose (CMC-Na). The cuprizone model was induced via feeding with the diet containing 2 g/L cuprizone. We administrated DHTS1 to the cuprizone-exposed mice. The mice were randomly divided into CMC-Na normal group, CMC-Na combined with cuprizone group and DHTS1 combined with cuprizone group. Myelin degeneration was checked by Luxol fast blue (LFB) staining and the immunohistochemical staining of myelin basic protein (MBP) and myelin proteolipid (PLP). Cell apoptosis was measured by TUNEL. Microglia polarization was evaluated by Iba-1, CD86 and CD163 immunohistochemical staining in vivo. The SIM-A9 cells cultured were divided into CMC-Na group, DHTS1 group, CMC-Na combined with LPS group and DHTS1 combined with LPS group. The expression of CD16/32, tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) was analyzed by flow cytometry in vitro. Results Compared with CMC-Na combined with cuprizone group, DHTS1 treatment significantly attenuated myelin loss and cell apoptosis, reduced the area of Iba-1+ amoebic microglia and the number of CD86+ cells, while increased the number of CD163+ cells in the corpus callosum area of the brain. In addition, compared with CMC-Na combined with LPS group, DHTS1 obviously decreased the percentages of CD16/32+, iNOS+, TNF-α+ microglia. Conclusion DHTS1 can suppress cuprizone-induced demyelination and cell apoptosis through regulating the microglia polarization and mitigating inflammatory reaction in the central nerve system.