Zinc-α2-glycoprotein (ZAG) is decreased in neurons of epilepsy patients and models. Either insulin or overexpressing ZAG suppresses seizure and epileptiform discharges. ZAG is known to influence insulin sensitivity of tissues, but whether insulin regulates ZAG is unknown. This study investigated the effect and mechanism of insulin on ZAG expression and epileptiform discharge-induced oxidative stress. Primary cultured cortical neurons were treated with insulin, AXL1717 (inhibitor of insulin-like growth factor-1 receptor), or BMS-754807 (inhibitor of both insulin receptor and insulin-like growth factor-1 receptor). Mg-free epileptiform discharge model was also made. Levels of ZAG and AZGP1 mRNAs in neurons were measured. Oxidative stress in Mg-free-treated treated neurons underwent AZGP1 knock-down, AZGP1 overexpression, or insulin treatment was determined. Insulin treatment increased ZAG expression in neurons; this insulin-induced ZAG increase was abolished by either AXL1717 or BMS-754807. Either insulin treatment or ZAG overexpression suppressed epileptiform discharge-induced oxidative stress in neurons. Knock-down of ZAG abolished the antioxidative stress effect of insulin. Insulin-induced ZAG increase in neurons was mainly related to the activation of insulin-like growth factor-1 receptors. Insulin presented its antioxidative stress effect in neuronal epileptiform discharge models by increasing ZAG.