Abstract Background: Cerebellum is the region of brain responsible for multiple motor and cognitive functions. It is formed of two cerebellar hemispheres separated by fissures. It is formed of lobes, lobules and folia; each folium is formed of cerebellar cortex and medulla. Methotrexate is anti-metabolic drug used in treatment of cancer, it has neurotoxic effect, and it produces oxidative stress in nervous tissue. Vitamin C is powerful anti-oxidant; it is a powerful free radical scavenger. Aim of Study: The aim of this work is to study the toxic effects of methotrexate and the possible protective role of vitamin C. Material and Methods: In this study, 30 rats are divided in to 3 groups (Group 1) received no treatment. (Group 2) received 10mg/kg methotrexate injected intraperitoneal once time per week foe four weeks. (Group 3) received vitamin C 20mg/kg by intragastric tube every other day for four weeks and methotrexate as same dos of group 2. At the end of experiment, rats are sacrificed and cerebella are taken and processed for light microscopic examination. Results: There are histological changes in group treated with methotrexate (2) in the form of decreased thickness of granular layer. Purkinje cells shows shrinkage in cell bodies, decrease in number, lost mono laminar organization. Molecular layer showed decreased cellularity. After administration of vitamin C, these cellular changes are decreased, molecular and granular cell layer thickness are restored. Conclusion: Methotrexate is a toxic drug, it destroys the cerebellar cortex, but when administrated with vitamin C, its toxicity is decreased.