Microglia, the resident immune cells of the central nervous system (CNS), are critically involved in the pathogenesis of multiple sclerosis (MS). To better understand the molecular changes in these cells during neuroinflammation, we performed high-depth quantitative proteomics on microglia isolated from a murine model of MS, experimental autoimmune encephalomyelitis (EAE). This dataset provides a comprehensive proteomic landscape of EAE microglia, offering valuable insights into the cellular mechanisms driving MS pathology.