Objective: L-thyroxine is used for control and prevention of many thyroidal diseases, though it may cause damages in thyroid hormone-sensitive organs, namely, liver and kidney. Reports on the protective effects of any antioxidants in L-thyroxine induced oxidative stress are scanty. Thus, L-thyroxine induced oxidative stress and its prevention by Vitamin E supplementation have been studied in the present investigation. Methods: Adult, male Wister rats were divided into four groups of six animals each, and L-thyroxine (T4) (0.3 mg/kg body weight) was administered intraperitoneally in the treated group. Similarly, L-thyroxine (T4), at the above-mentioned dose, and Vitamin E acetate (100 mg/kg of body weight/ day orally) coadministered simultaneously (T4+VE) in the next group. Third group was administered only with Vitamin E, and the remaining group kept as control. Treatment continued regularly for 15 and 30 days. Animals were sacrificed after completion of treatment. Lipid peroxidation (LPO) level, superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) activities were assayed in liver and kidney along with their histology. Obtained results were interpreted statistically against their respective control groups. Results: Body weight was significantly decreased and relative kidney weight was increased after L-thyroxine administration as compared to control (p<0.05). LPO level, SOD and catalase activities were significantly enhanced in L-thyroxine treated groups, whereas GPx activity was decreased. However, LPO level and the activities of those enzymes along with body weight and organ weights were almost restored their normal in L-thyroxine and Vitamin E coadministered group treated for 15 days and 30 days, respectively. Conclusion: Exogenously administered L-thyroxine causes oxidative stress in liver and kidney that in turn generates reactive oxygen species resulting cell damages. Vitamin E acetate supplementation reduces these adverse effects on liver and kidney and thus acts as a beneficial health management agent. © 2018 The Authors.