Multiple sclerosis (MS) is an autoimmune disease characterized by infiltration of peripheral immune cells into the central nervous system, demyelination, and neuronal damage. There is no cure for MS, but available disease-modifying therapies can lessen severity and delay progression. However, current therapies are suboptimal due to adverse effects. Here, we investigate how the FDA-approved antihypertensive drug, guanabenz, which has a favorable safety profile and was recently reported to enhance oligodendrocyte survival, exerts effects on immune cells, specifically microglia and macrophages. We first employed the experimental autoimmune encephalomyelitis (EAE) model and observed pronounced immunomodulation evident by a reduction in pro-inflammatory microglia and macrophages. When guanabenz was administered in the cuprizone model, in which demyelination is less dependent upon immune cells, we did not observe improvements in remyelination, oligodendrocyte numbers, and effects on microglial activation were less dramatic. Thus, guanabenz may be a promising therapeutic to minimize inflammation without exerting severe off-target effects.