Objective: This study aimed to explore the hepatotoxicity induced by silver nanoparticles (AgNPs) and to assess the hepatoprotective effects of α-lipoic acid (LA) against this toxicity. Methods: Thirty adult male rats were enrolled into 3 equal groups; Control, AgNPs (50 mg/kg/i.P) and LA (100 mg/kg/orally) +AgNPs. After 30 days, blood and liver tissues were collected for further studies. Results: AgNPs exposure enhanced lipid peroxidation(+281.7%) along with declines in glutathione (−58.3%) Level in hepatic tissues. The apparent hepatic oxidative damage was associated with obvious hepatic dysfunction that was ascertained by hepatopathological lesions.As, following AgNPs exposure, hepatic silver content and serum ALT, AST and ALP activities were increased, moreover allows calcium influx and induces intracellular calcium overload. Hepatic tissues treated with AgNPs showed down-regulation of all the genes considered (PGC-1α, Tfam and Nrf2).LA improved the serious effects of AgNPs on the liver tissues through its antioxidant andmetal chelator efficacy. Conclusion: Silver nanoparticles (AgNPs) can induce hepatotoxicity along with oxidative stress, substantial decrease in cell viability with concomitant increases in DNA damage. Oral treatment with LA effectively counteracted the adverse effects of AgNPs.