Demyelination and autoimmune chronic inflammation in the central nervous system are the typical pathological features of multiple sclerosis (MS). A range of immune and nerve cells participate in the disease process of MS. The regulation of inflammation and remyelination is mainly performed by microglia ( MG) and oligodendrocyte precursor cells (OPCs), respectively. In non-repairing lesions of MS patients, an imbalance of MG polarization and a failure of OPC differentiation are likely to contribute to inefficient remyelination. Previous researchers have emphasized that these are independent functions. However, it has recently been reported that MG polarization is closely connected with OPC differentiation, an imbalance of MG polarization can inhibit OPC differentiation. Conversely, OPCs can also interfere with the inflammatory response of MG. Taken together, interactions between MG and OPCs form a holistic entity and function as a crucial mechanism of remyelination. Currently approved treatments for MS mainly target the aberrant immune response, and are able to improve the disease-related symptoms but do not cure MS, particularly intractable secondary progressive multiple sclerosis ( SPMS ). Therapeutic strategies or agents that promote remyelination remain under extensive investigation. This review summarizes the interactions between MG polarization and OPC differentiation, and provides strategies to overcome the failure of OPC differentiation by attempting to rebalance MG polarization, which will be beneficial for the development of demyelinating diseases including SPMS.