Among the multiple kinds of neuronal cell death triggered by traumatic brain injury (TBI), ferroptosis, an iron-dependent lipid peroxidative regulatory cell death, has a critical role. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear transcription factor that regulates lipid metabolism and suppresses neuronal inflammation. However, the role of PPARγ in neuronal ferroptosis induced by TBI remains unclear. Here, we investigated the regulatory effect of PPARγ on neuronal ferroptosis in a weight-drop TBI model in vivo and an RAS-selective lethal 3 (RSL3)-activated ferroptotic neuronal model in vitro. PPARγ was mainly localized in the nucleus of neurons and was decreased in both the in vivo TBI model and the in vitro ferroptotic neuronal model. The addition of a specific agonist, pioglitazone, activated PPARγ, which protected neuronal function post-TBI in vivo and increased the viability of ferroptotic neurons in vitro. Further investigation suggested that PPARγ probably attenuates neuronal ferroptosis by downregulating cyclooxygenase-2 (COX2) protein expression levels in vivo and in vitro. This study revealed the relationship among PPARγ, ferroptosis and TBI and identified a potential target for comprehensive TBI treatment. •PPARγ is mainly distributed in the nucleus of neurons.•TBI causes downregulation of PPARγ expression with activation of ferroptosis activation.•Pioglitazone reduces neuronal loss after TBI by inhibiting ferroptosis.•PPARγ reduces neuronal ferroptosis by blocking COX2 expression.