Multiple sclerosis (MS) is an irreversible and demyelinating disease of the central nervous system, in part influenced by chronic inflammation. There is no proven effective therapy to stop the pathological progression of MS, although suppressing the immune system to control the inflammatory response may improve the clinical performance acutely. Here, we found that mesenchymal stem cells from human umbilical cord (hUC-MSCs) could restore behavioral functions and attenuate the histopathological deficits of experimental autoimmune encephalomyelitis mice over the long term (i.e., 50 days) by suppression of perivascular immune cell infiltrations and reduction in both demyelination and axonal injury in the spinal cord. These findings suggest that transplantation of hUC-MSCs may be a potential therapy for MS.