Mitochondrial dysfunction is thought to be involved in the pathogenesis of MS and here we tested if brain penetrant mitochondrial uncouplers, DNP (MP101) and a novel prodrug of DNP (MP201), have the pharmacology to suppress demyelination and axonal loss in two independent models of MS by modulating the entire organelle’s physiology. First, the gold standard EAE mouse model for MS was evaluated by daily oral treatment Day 7-21 with either MP101 or MP201 post-immunization. Both MP101/MP201 significantly suppressed progression of paralysis with limited infiltration of inflammatory cells. Strikingly, although mitochondrial uncouplers do increase energy expenditure even at the low doses provided here, they paradoxically preserved body weight at all doses in comparison to wasting in advanced paralysis of the placebos. Second, the effects of the compounds on suppressing inflammation were also evaluated in the cuprizone model, independent of the immune system. MP101/MP201 had a striking effect preserving both myelination and protecting the axons, in comparison to the placebos where both were destroyed. Both MP101/MP201 induced a significant and sustained increase in neurotrophin, BDNF, in the spinal cords. Both MP101/MP201 suppressed the expression of inflammatory cytokines including IL-1β, TNF-α and iNOS. Results indicate that MP101/MP201 may be a “disease modifying” treatment for MS by specifically modulating mitochondrial physiology. This would be a completely novel treatment for MS, targeting the mitochondria directly using a unique platform, mitochondrial uncouplers, that initially act non-genomically based upon biophysics, but cascades into cellular remodeling, neuroprotection and pro-survival. Clinical Phase I testing of MP101 in Normal Healthy Volunteers (NHV) is currently underway allowing for the potential to subsequently evaluate translation in MS patients and other insidious diseases, at expected weight neutral doses.