Toll-Like Receptor 4 (TLR4) is a relevant actor for innate immunity involved in inflammatory responses in Multiple Sclerosis (MS) and other diseases. The currently available therapeutic arsenal to treat MS is composed of immunomodulators but, to date, there are no (re)myelinating drugs available in clinics. In the present work, we study the effect of TLR4 inhibition in different animal models of MS.The experimental autoimmune encephalomyelitis (EAE) model was used to evaluate the effect of TLR4 inhibition on reducing the inflammatory component. A more direct effect on oligodendroglia was studied with the cuprizone model and purified cultures of murine and human oligodendrocyte precursor cells (OPCs) isolated from samples of brain cortex. TLR4 inhibition treatment positively impacted the clinical symptomatology of mice from EAE and cuprizone models, which was associated with better preservation plus restoration of myelin and oligodendrocytes in the demyelinated lesions of animals. This was corroborated on purified cultures of rodent and human OPCs.In conclusion, TLR4 inhibition has an anti-inflammatory and cytoprotective effect in animal models of MS. Furthermore, inhibition of TLR4 leads to better remyelination in such models. Our current findings reveal a new therapeutic approach for the treatment of inflammatory and demyelinating diseases such as MS.