In response to corpus callosum (CC) demyelination, subventricular zone-derived neural progenitors (SVZdNP) are mobilized and generate new myelinating oligodendrocytes. Here, we examine the putative immunomodulatory properties of endogenous SVZdNP during demyelination in the cuprizone model. We observed that SVZdNP density is higher in the lateral and rostral CC regions that show weaker demyelination and is inversely correlated with activated microglia density and pro-inflammatory cytokines levels. Single-cell RNA-sequencing further revealed CC areas with high SVZdNP mobilization are enriched in a microglial cell subpopulation with immunomodulatory signature. We identified ligand/receptor couple MFGE8 (milk fat globule-epidermal growth factor-8)/integrin β3 as a ligand/receptor couple implicated in SVZdNP/microglia dialog. MFGE8 is highly enriched in immature SVZdNP mobilized to the demyelinated CC and promotes myelin debris phagocytosis in vitro. Altogether these results demonstrate that beyond their cell replacement capacity endogenous progenitors display immunomodulatory properties highlighting a new role for endogenous SVZdNP in myelin regeneration.