Microglia are the inherent macrophages and immune surveillance cells in the central nervous system (CNS) and compose the first guard of immune defense in CNS. The activation of microglia is one of the pathological features of many CNS diseases and acts as an important role during the multiple sclerosis (MS) process. MS is a CNS disease characterized by neuroinflammatory infiltration, demyelination and axonal damage. Accumulation of activated microglia at the injury site has been observed in brains of MS patients and experimental animals with complicated mechanisms. Microglia have both detrimental and beneficial roles. For instance, microglia have been shown to recruit and reactivate T cells in the CNS and release many detrimental molecules such as proteases, inflammatory cytokines, and free radicals. Conversely, they have also been observed to aid in axonal regeneration and remyelination as well as assist in the clearance of inhibitory myelin debris. In addition, microglia have been shown to release a variety of neurotrophic factors. Cuprizone[oxalic acid bis(cyclohexylidene hydrazide)] is a well-known copper-chelating agent. Cuprizone ingestion in mice induces a highly reproducible demyelination of distinct brain regions. Discussion on the detrimental and beneficial aspects of microglia in cuprizone animal models will serve to better understand the development of MS and find out new therapeutic targets. This review will further our understanding of the dichotomous roles of microglia in cuprizone-induced demyelination in animal models of multiple sclerosis.