This study investigated the molecular mechanisms underlying lead (Pb)-induced nephropathy and assessed the nephroprotective potential of Polydatin (PD). Forty male Wistar rats were divided into five groups (n = 8/group): negative control (NC), normal rats treated with 200 mg/kg/day of PD (NPD200), positive control (PC) receiving Pb only (30 mg/kg/day), and two groups co-administered Pb with PD (100 or 200 mg/kg/day). Serum and urine Pb levels were determined by an atomic absorption spectrophotometer. Markers of renal tissue damage (TGF-β/iNOS/NGLA/KIM-1) and renoprotective molecules (Nrf2/AMKα/AKT1) genes and proteins were measured by quantitative RT-PCR and Immunohistochemistry, respectively. ELISA was used to quantify markers of oxidative stress (GSH/Gpx1/CAT/MDA/H