Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by progressive neuronal demyelination and degeneration. Much of this damage can be attributed to microglia, the resident innate immune cells of the CNS, as well as monocyte-derived macrophages, which breach the blood-brain barrier in this inflammatory state. Upon activation, both microglia and macrophages release a variety of factors that greatly contribute to disease progression, and thus therapeutic approaches in MS focus on diminishing their activity. We use the CSF1R inhibitor PLX5622, administered in mouse chow, to ablate microglia and macrophages during the course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that ablation of these cells significantly improves animal mobility and weight gain in EAE. Further, we show that this treatment addresses the pathological hallmarks of MS, as it reduces demyelination and immune activation. White matter lesion areas in microglia/macrophage-depleted animals show substantial preservation of mature, myelinating oligodendrocytes in comparison to control animals. Taken together, these findings suggest that ablation of microglia/macrophages during the symptomatic phase of EAE reduces CNS inflammation and may also promote a more permissive environment for remyelination and recovery. This microglia and macrophage-targeted therapy could be a promising avenue for treatment of MS.