This study investigates the exposure of lead-induced reactive oxygen species (ROS) generation, DNA damage, and apoptosis and also evaluates the therapeutic intervention using antioxidants in human renal proximal tubular cells (HK-2 cells). Following treatment of HK-2 cells with an increasing concentration of lead nitrate (0-50 μM) for 24 h, the intracellular ROS level increased whereas the GSH level decreased significantly in a dose-dependent manner. Comet assay results revealed that lead nitrate showed the ability to increase the levels of DNA strand breaks in HK-2 cells. Lead exposure also induced apoptosis through caspase-3 activation at 30 μg/mL. Pretreatment with N-acetylcysteine (NAC) and tannic acid showed a significant ameliorating effect on lead-induced ROS, DNA damage, and apoptosis. In conclusion, lead induces ROS, which may exacerbate the DNA damage and apoptosis via caspase-3 activation. Additionally, supplementation of antioxidants such as NAC and tannic acid may be used as salvage therapy for lead-induced DNA damage and apoptosis in an exposed person.