The kidney is one of the main organs affected by lead toxicity. We investigated the effects of berberine on lead-induced nephrotoxicity in adult male Wistar rats. Animals received an aqueous solution of lead acetate (500 mg Pb/L in the drinking water) and/or berberine (50 mg/kg, i.g.) for 8 weeks. Lead caused an increase in malondialdehyde (P < 0.001) and total oxidant status (P < 0.01), and a decrease in reduced glutathione (P < 0.001), catalase (P < 0.01), superoxide dismutase (P < 0.001), and total antioxidant capacity (P < 0.05). Berberine prevented the prooxidant and antioxidant imbalance induced by lead (P < 0.001). Berberine corrected the increased relative kidney weight (P < 0.05) and biomarkers of renal function (creatinine (P < 0.001), urea (P < 0.05), uric acid (P < 0.001), albumin (P < 0.01), and total protein (P < 0.05)) in lead group. It also attenuated lead-induced abnormal renal structure. The results confirmed renoprotective effects of berberine in an animal model of lead-induced nephrotoxicity by molecular, biochemical, and histopathological analysis through inhibiting lipid peroxidation and enhancing antioxidant defense system mechanisms. Therefore, berberine makes a good candidate to protect against the deleterious effect of chronic lead intoxication.