The present research task is aimed to evaluate the role of exogenous α-lipoic acid (ALA) (100 mg/kg body weight) as hepatoprotective and potent antioxidant in amelioration of copper nanoparticle (CNP)-induced hepatotoxicity. Forty male rats were randomly assigned into four equal groups: group I (control), group II received CNPs, group III received CNPs + ALA, and finally group IV received ALA for 2 months. At the end of the experimental period, the rats were decapitated, and blood and liver tissue samples were collected for measurement of liver function tests, antioxidant status, lipid peroxidation (LPO), copper content, expression of some apoptotic genes, and histopathological analysis. CNPs induced marked hepatic damages as evident by severe alteration in hepatic biomarkers. This was accompanied by a significant elevation in hepatic LPO and induced nitric oxide, copper content, and expression level of apoptotic genes (C-myc and C-jun). In contrast, marked depletion for antioxidant parameters was detected. These findings were confirmed with severe pathological alterations. Coadministration of ALA as a powerful antioxidant attenuates the hepatotoxic effects of CNPs through improvement of liver parameters, oxidative status, genetic changes, and preservation of liver integrity through histopathological analysis. These results suggest that consumed ALA could be used as an applicable hepatoprotective agent against oxidative damage mediated by nanoparticles intoxication.