Introduction: Multiple sclerosis (MS) is an autoimmune disease, which is characterized by multifocal demyelination of axons in the CNS. Complications due to the disease, as well as the use of immunosuppressive drugs, antidepressants, etc., lead to some abnormalities. These drugs predispose to oral bleeding and are particularly susceptible to infection. The main side effects of drugs in the oral cavity are stomatitis, ulcers, gingivitis, candidiasis, and some opportunistic infections (such as herpes simplex). Dentists should also be aware of the importance of the disease in the diagnosis, treatment, and prognosis of some lesions as well as its specific conditions. Hence, in this study, the histopathological changes of the oral mucosa and salivary glands were studied on C57BL/6 demyelination mice (multiple sclerosis model).Material & method: The histological changes in parotid, submandibular, and sublingual glands were studied in both control (intact) and demyelination models of mice. The present study, 20 mice C57BL/6 were divided into two groups: 1) sham group (fed regular chow); 2) demyelination group (received rodent chow mixed with 0.2% cuprizone for 12 weeks). Seven weeks after demyelination inflammation (Hematoxylin-eosin), fibrosis (Masson’s Trichrome), and mast cells granulation (toluidine blue) were examined. Result: Our results demonstrated inflammation in the major salivary gland 12 weeks after demyelination. Also, the increase in fibrosis and decrease in vascularization was observed in buccal mucosa of different areas (P<0.05). The keratinization reduced in demyelination group (P<0.05). The expression of GFAP in the major salivary gland was significantly decreased in the demyelination group (P<0.05). Conclusions: MS may be a risk factor for oral lesions such as inflammation, fibrosis, and ulcer. These data present the pathological effect of demyelination on acini and ductal region in salivary glands.