OBJECTIVE: The purpose of this work was to investigate whether resveratrol affects lead-induced oxidative damage in HT-22 cells, characterizing mechanisms and strategies for preventing and treating lead-induced neurotoxicity. METHODS: Various lead and resveratrol concentrations were applied to HT-22 cells over different time periods. First, we established the lead treatment (12.5, 50 and 200 μmol/L) and resveratrol (40 μmol/L) intervention model for the study. MTT was used to analyze HT-22 cell survival rate. The rates of cell death, mitochondrial membrane potential, lipid peroxidation, and reactive oxygen species (ROS) generation were all measured by flow cytometry. Cellular oxidant (MDA) and antioxidant (SOD, GSH-Px) levels were measured with test kits. Western blotting was used to assess the expression of proteins related to autophagy and apoptosis. RESULTS: Lead reduced HT-22 cell viability in a concentration/time-dependent manner. In addition, lead (200 μmol/L) decreased the protein expression of BCL2, while increasing PARP and BAX expression and apoptotic rate. Moreover, the lead-exposed group had significantly higher levels of ROS, lipid-ROS, and MDA than the control group. This was accompanied by increased MDA levels and decreased SOD, GSH-Px, and MMP levels in the lead-exposed cells. Furthermore, lead lowered SIRT1 protein expression, while increasing the levels of autophagy-related proteins, including P62, ATG5, Beclin-1 and LC3 Ⅱ/Ⅰ. Resveratrol (40 μmol/L), an agonist of SIRT1, restored the effects of lead (200 μmol/L) to levelsindistinguishable from controls. CONCLUSION: Resveratrol inhibited mitochondrial damage and restored the lead-induced block of autophagic flux and oxidative stress by activating SIRT1, thereby alleviating lead-induced damage in HT-22 cells.