BACKGROUND: Boosting myelin repair is widely recognized as one of the most powerful approaches for demyelinating therapy, essentially contributing to the recovery of neurological functions. Maintaining immune homeostasis in microglia is a prerequisite for creating a reparative environment for myelin. Dihydroartemisinin (DHA) is clinically effective in reshaping immunological status and implies potential in treating demyelinating disease. However, its relevance to pro-remyelination remains unclear. METHODS: We first evaluated the effects of DHA on neurofunctional recovery and white matter integrity in chronic experimental autoimmune encephalomyelitis (EAE), an ideal model for secondary progressive multiple sclerosis (SPMS) characterized by remyelination deficiency. Single-cell sequencing and microglial depletion with PLX3397 in vivo were used to reveal the dependency between DHA and microglia. The effect of DHA on the reparative phenotype of microglia, particularly on cholesterol recycling and differentiation of oligodendrocyte progenitor cells (OPCs), was evaluated in microglia-OPCs unit either in vitro or in vivo challenged with myelin debris. Finally, to broaden the clinical application for DHA in myelin repair, it was tested in the cuprizone (CPZ) model which shows remyelination failure, a condition common in various neurodegenerative diseases. RESULTS: We demonstrated for the first time that DHA enhanced white matter integrity and OPCs proliferation and differentiation. This effect is dependent on the transition of microglia to a reparative phenotype. Specifically, DHA increased the secretion of inflammatory-resolving and neurotrophic cytokines. It further functionalized cholesterol recycling and provided metabolic support for myelin regeneration predominantly mediated by liver X receptor (LXR) in microglia. This was evidenced by the promotion of myelin debris uptake, cholesterol catabolism, efflux and transport. Notably, DHA promoted remyelination and neurological functional recovery in CPZ-induced demyelinating model, supporting its potential application in neurodegenerative diseases featuring insufficient remyelination. CONCLUSION: By highlighting the importance of microglia in promoting myelin regeneration, our study proved DHA as a promising candidate for promoting remyelination.