<p>Lead toxicity poses a serious threat facing humanity. Research aims to investigate the potential hepato-protective effect of <em>Physalis peruviana</em> (P.P) fruit against lead toxicity (10 ppm (1/45 LD50)) in male albino rats. Toxicological induction with lead acetate lasted for 28 days followed by treatment with 200, 300, and 500 mg/kg of lyophilized P.P. fruit extract for another 28 days. Superoxide dismutase, malonaldehyde, catalase, and glutathione peroxidase were measured using a spectrophotometer. Lead concentration in liver tissues was assessed using Atomic Absorption Spectroscopy after four and eight weeks, in addition to Aspartate aminotransferase, alanine aminotransferase, and complete blood count were measured. Lead acetate induced a substantial elevation in malonaldehyde levels, and a significant decrease in Superoxide dismutase, catalase, and glutathione peroxidase activities. Treatment with 200, 300, and 500 mg/kg P.P showed an improvement in the activity of the antioxidant enzymes in a dose-dependent manner. Co-administration of P.P. ameliorates the damage caused by lead acetate. <em>Physalis peruviana</em> solution showed a reduction in the mean lead concentration in a dose-dependent response of 0.26±0.02, 0.21±0.02, and 0.14±0.03 ppm for groups III, IV, and V, respectively. In conclusion, P.P. fruit extract can improve antioxidant activity and exert a beneficial effect in the treatment of Pb-induced hepatotoxicity.</p>