The aim of this study was to investigate the role of hydroxychloroquine (HCQ)-induced oxidative stress on sciatic nerve and muscle tissues of rats. The oxidant/antioxidant parameters in the sciatic nerve and muscle tissues were analyzed, and stereological analysis of the sciatic nerve was performed. Levels of malondialdehyde and nitric oxide in the tissues were significantly higher in the HCQ group than in the control group (p < 0.05). In addition, activities of superoxide dismutase and glutathione peroxidase were found to be significantly higher in the HCQ group than the control group (p < 0.05). There were significant decreases in nerve fiber diameter and myelin sheet thickness in the HCQ group compared with the control group (p < 0.05). These results revealed that HCQ might increase oxidative stress on sciatic nerve and muscle tissues of rats, which may correlate with axonal atrophy in sciatic nerves.