A 2 × 3 factorial experiment was designed to study the effect of sublethal toxicity of technical grade copperoxychloride, dietary vitamin E, and their interaction on growth performance, some blood parameters, DNA fragmentation, and histopathological lesions of Nile tilapia (Oreochromis niloticus). The 96-h lethal concentration 50 (LC₅₀) of copperoxychloride was found to be 129.21 mg/l. Four hundred and fifty fingerlings with an average initial body weight ranging from 1.92 to 2.04 ± 0.11 g were randomly distributed equally in six treatments (T1 to T6) with each in triplicate. T4, T5, and T6 were exposed to sublethal concentration 0.25 LC₅₀ of copperoxychloride. Fish in T1, T2, and T3 fed diet supplemented with different levels of vitamin E (0, 1, and 2 g/kg diet), respectively, while fish of T4, T5, and T6 fed diet supplemented with different levels of vitamin E (0, 1, and 2 g/kg diet), respectively. At the end of the experiment (90 days), the results indicated that fish exposed to 0.25 LC₅₀ of copperoxychloride and fed diet with normal level of vitamin E showed significantly (P < 0.01) lower values of all growth and feed utilization parameters, white blood cells, and immunoglobulin M, but they showed significantly (P < 0.05) increased values of alanine aminotransferase, aspartate aminotransferase, hematocrit, hemoglobin, uric acid, and creatinine. Varied concentrations of vitamin E neutralized the toxic effect of copperoxychloride as well as significantly lowered the hematological and biochemical responses and enhanced the growth and feed utilization parameters. The toxic effect of copperoxychloride exposure and vitamin E feeding on the histopathology of the liver and gill of the same studied fish will be taken in concern. The results showed improvement in samples treated with vitamin E. This study suggests that vitamin E can be effectively used to decrease the toxic effect of copperoxychloride on O. niloticus and its amelioration through dietary vitamin E supplementation.