The kidney plays an important physiological function, maintaining the osmoregulation and electrolyte balance of Nile tilapia (Oreochromis niloticus). Selenium and α-tocopherol (α-toc) are potent antioxidants, which improve the aquaculture health. In this study, we tested the potential ability of selenium and α-toc to alleviate the oxidative stress in the kidney induced by lead toxicity. Two hundred and twenty-five O. niloticus were divided into five groups. The control group received a basal diet. Lead nephrotoxicity was induced by daily application of 73.40 mg lead acetate/liter water for up to 10 weeks. Selenium and α-tocopherol were given 1 week before lead intoxication. Selenium was administered as sodium selenite, 4 mg/kg dry diet. Alpha-tocopherol acetate was administered as α-toc, 200 mg/kg dry diet. The last group received a mixture of selenium and α-toc in diet. Fish treated with selenium and/or α-toc (groups III-V) showed an amelioration of the adverse effects of lead toxicity and significant improvement in serum electrolytes (calcium, inorganic phosphate, and magnesium) and creatinine level compared with the positive control group (P ≤ 0.05). Treated groups showed significant decrease in superoxide dismutase (SOD) and reduced glutathione (GSH) activity with significant increase in malondialdehyde (MDA; P ≤ 0.05). It could be concluded that selenium and α-toc have a potential antioxidant effect and have the ability to improve the kidney function after lead intoxication of O. niloticus.