Stinging nettle (Urtica dioica L.) has a nutritional & medicinal effects in all over the world; A wide spectrum of diseases has been associated with an edible plant Urtica dioica L. including cancer, arthritis, autoimmune diseases as immunological stimulatory, and diabetes. Hydrocortisone (HC) considered a vital drug in many cases as inflammation & arthritis although its side effects like immunosuppression that lead to declination of body resistance for any infection. This study was carried out to investigate protective effect of natural herbs such as Urtica dioica L. from side effects are resulted from using anti-inflammatory and oxidative stress-mediated such as HC. Twenty-eight male albino were classified into 4 groups as control negative group, control positive group that was injected with HC, group 3 that was injected with HC and treated with 10 % Urtica dioica L. powder, and group 4 that was injected with HC and treated with 20 % Urtica dioica L. powder. The results revealed that the treatment with Urtica dioica L. significantly improved the immune system parameters such as Immunoglobulin A (IgA), increased levels of reduced glutathione (GSH) and total antioxidant capacity (TAC). A significant declination of interleukin-6 (IL-6), tumor necrosis factor (TNF) and malondialdehyde (MDA) levels were obtained in HC group and these changes were reversed by treatment by using natural herbs (Urtica dioica L.). Although HC induced histopathological changes occurred, Urtica dioica L. prevented these effects. Conclusion: Urtica dioica L. may has immunomodulatory effects in HC-induced immunosuppressed by boosting immune system and reducing inflammation.