Objectives: Traumatic brain injury (TBI) is a major cause of disability and mortality that induces oxidative stress and apoptosis causing cellulardamage. Several animal models have shown paeonol to be a powerful antioxidant, antiapoptotic, and neuroprotective substance. This study aimedto investigate possible neuroprotective effects of paeonol in a rat TBI model.Materials and Methods: Thirty-two male rats were divided into four groups: control, trauma, vehicle, and paeonol groups. Trauma, vehicle, andpaeonol groups were subjected to closed-head, contusive weight-drop injuries. The vehicle (saline) or paeonol (50 mg/kg) was orally administered aspremedication for 15 days. Brain samples were obtained 24 hours after trauma. Histomorphological evaluation of the cerebral cortex was performedusing electron and light microscopy.Results: Histopathological examination revealed that the TBI-induced cerebral cortex damage was less in the paeonol group.Conclusion: Paeonol exhibited neuroprotective and anti-edematous effects against TBI.