Traumatic brain injury (TBI) is a major cause of preventable death and morbidity in young adults. This complex condition is characterized by a significant blood-brain barrier leakage that stems from cerebral ischemia, inflammation, and redox imbalances in the traumatic penumbra of the injured brain. Recovery of function after TBI is partly through neuronal plasticity. In order to test whether combination therapy with melatonin and dexamethasone (DEX) might improve functional recovery, a controlled cortical impact (CCI) was performed in adult mice, acting as a model of TBI. Once trauma has occurred, combating these exacerbations is the keystone of an effective TBI therapy. The therapy with melatonin (10 mg/kg) and DEX (0.025 mg/kg) is able to reduce edema and brain infractions as evidenced by decreased 2,3,5-triphenyltetrazolium chloride staining across the brain sections. Melatonin- and DEX-mediated improvements in tissue histology shown by the reduction in lesion size and an improvement in apoptosis level further support the efficacy of combination therapy. The combination therapy also blocked the infiltration of astrocytes and reduced CCI-mediated oxidative stress. In addition, we have also clearly demonstrated that the combination therapy significantly ameliorated neurological scores. Taken together, our results clearly indicate that combination therapy with melatonin and DEX presents beneficial synergistic effects, and we consider it an avenue for further development of novel combination therapeutic agents in the treatment of TBI that are more effective than a single effector molecule.