Introduction: Epigenetic advances have led to the production of a specific class of medicines called epigenetic drugs, medications that inhibit histone deacetylase (HDACi). Valproic acid (VPA), known as HDACi, has neuroprotective effects. The current study investigated the histological and functional changes of a demyelination model associated with VPA treatment in C57BL/6 mice. Material & method: In the present study, 48 C57BL/6 mice were classified randomly into eight groups: sham, cuprizone (0.2%), three VPA groups (treated with 100, 200, and 300 mg/kg of VPA), three groups of cuprizone plus VPA (100, 200, and 300 mg/kg of VPA). One week after treatment, gliosis, apoptosis, and remyelination were examined histologically, and locomotor function was assessed by the behavioral test. Result: The expression of GFAP and caspase-3 in the untreated controls had the highest immunofluorescence, while it was significantly decreased in the VPA groups (P<0.05). The lowest expression of these two markers was observed in the 200 mg/kg VPA group, which also had the highest expression of MBP. Behavioral tests showed that mice in the 200 mg/kg VPA group achieved the highest score and the results of the histological examination were consistent with the results of the behavioral test. Conclusion: The data demonstrated that there was an improvement of the demyelination models of mice treated with an optimal dose of VPA, characterized by an increase in remyelination and an increase in the behavioral score.