Epilepsy is commonly associated with cognitive impairment. Astrocyte activation and oxidative stress occur following seizures, and play a role in the pathological injury of epilepsy with cognitive impairment. The peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to exhibit neuroprotective and antioxidative effects in CNS diseases. Thus, we hypothesized that rosiglitazone, a PPARγ agonist, would prevent cognitive impairment by inhibiting astrocyte activation and regulating glutathione (GSH) homeostasis after status epilepticus (SE). Using a lithium pilocarpine-induced SE model, we found that rosiglitazone significantly prevented cognitive impairment induced by SE, and potently inhibited astrocyte activation with maintenance of GSH homeostasis in the hippocampus after SE. These protective effects were significantly reversed by co-treatment with the PPARγ antagonist T0070907. These data suggest that rosiglitazone can improve cognitive impairment, and inhibit astrocyte activation and oxidative damage following SE. Rosiglitazone may be a promising agent for treatment of epilepsy involving SE-induced cognitive impairment.