Traumatic brain injury (TBI) is a major risk factor to develop epilepsy and cognitive impairments. Neuropeptide oxytocin has been previously evidenced to produce antiepileptic effects. However, the involvement of central oxytocin in TBI-induced epileptic status and cognitive dysfunctions is not fully elucidated. In this study, we aim to investigate the role of oxytocin on a TBI model followed by seizure induction to clarify whether the epilepsy and cognitive deficits could be mitigated by oxytocin. TBI was established by weight drop and epileptic behaviors were induced by pentylenetetrazole (PTZ) injection in mice. Moreover, oxytocin was microinjected into the medial prefrontal cortex (mPFC) to observe the effects on the epilepsy and cognition. The blood-brain barrier (BBB) function and the neuroinflammation were measured by Evans Blue staining and enzyme-linked immunosorbent assays, respectively. Mice exposed to TBI demonstrate increased vulnerability to PTZ-mediated seizures and cognitive disturbances with a decrease in peripheral and brain oxytocin levels. Additionally, TBI reduces oxytocin, disrupts the BBB permeability and triggers neuroinflammation in mPFC in PTZ-treated mice. Intra-mPFC oxytocin simultaneously mitigates epilepsy and cognitive impairments. Finally, oxytocin restores BBB integrity and reduces mPFC inflammation in PTZ-treated TBI mice. These findings showed that intra-mPFC oxytocin suppressed the seizure vulnerability and cognitive deficits in TBI mice. The normalization of BBB integrity and inhibition of neuroinflammation may be involved in the antiepileptic and cognition-improved effects of oxytocin, suggesting that targeting inflammatory procedure in mPFC may decrease the risk to develop epilepsy and cognitive impairments in individuals previously experienced TBI.