This study was intended to investigate whether dietary supplementation with different levels of nano-selenium (NSE) may reverse the negative influences of lead (Pb) contamination on growth, whole body composition, Pb residue in the tissues, and blood components in Oreochromis niloticus. The fish (n=180; 16.97±0.71 g) were allocated randomly into six equal groups as follows; the first group was fed the control diet, and the second was fed on the control diet contaminated with 80 ppm Pb (LW). From the third to the sixth groups (NSE0.2, NSE0.3, NSE0.4, and NSE0.5) were fed LW diet fortified with NSE at 0.5, 1.0, 2.0, and 4.0 mg nano-selenium/kg diet, respectively for 112 days. Results showed that fish LW group displayed significantly impaired growth performance, feed intake, feed conversion, and blood biochemical (P≤0.01) compared with fish in the control group. In contrast, fish groups NSE0.2, NSE0.3, NSE0.4, and NSE0.5 had significantly increased final body weight, daily weight gain, relative growth rate, survival rate, and daily feed intake compared with fish in the LW group. Furthermore, feed conversion and Pb bioaccumulation in fish tissues as well as serum contents of creatinine, AST, and ALT were significantly decreased (P≤0.01) in enriched NSE groups compared to the LW group. However, a significant increase in the values of hemoglobin, total protein, and albumin was observed in all NSE supplemented groups. The maximum enhancement was noted in NSE0.5 in most of the tested parameters. In conclusion, supplementing O. niloticus diet with NSE at 0.2 to 0.5 mg/ kg diet ameliorated the negative impacts of Pb toxicity on growth indicators, Pb residue in the tissues, and blood components.