Multiple sclerosis (MS) results from the destruction of myelin and focal inflammation. The study aimed to evaluate the effect of hydroalcoholic extract of Urtica dioica on oxidative stress, heat shock proteins, and brain histopathology in multiple sclerosis model. Sixty male C57BL/6 mice were divided into six groups of 10.Groups included positive control, negative control, and treatment groups with U. dioica extract at a dose of 50, 100, 200, and 400 mg/kg for 21 days (three times a week). The MS model was developed by a diet containing 0.2% cuprizone for 6 weeks. A section of brains was evaluated with Luxol Fast Blue staining and the other part evaluated with heat shock protein (HSP) kits 60 and 70, total antioxidant capacity (TAC), and malondialdehyde (MDA). In sections of corpus callosum, the highest amount of myelin was observed in the negative controls, while the use of cuprizone in the positive controls caused the destruction and reduction of myelin. The use of U. dioica extract in therapeutic groups except at a dose of 50 mg/kg could reduce myelin degradation to some extent and lead to remyelination. However, myelin levels in treatment groups were not significantly different from any of the negative and positive controls. Although HSP60 decreased in the treatment groups, there was no significant difference between the positive and negative controls. Treatment with this extract significantly reduced the amount of HSP70 compared with the positive controls. The decreased TAC and increased MDA in positive controls indicated oxidative stress, respectively. Furthermore, the extract led to an increase and decrease of TAC and MDA in the treatment groups, respectively. However, only the MDA level was significantly different from that of the positive controls. Therefore, the antioxidant effects of U. dioica