Objective(s): Traumatic brain injury (TBI) is one of the most common causes of death and disability in modern societies. The role of steroids and melatonin is recognized as a neuroprotective factor in traumatic injuries. This study examined the role of melatonin receptors in the neuroprotective effects of estrogen. Materials and Methods: Seventy female ovariectomized Wistar rats were divided into five groups and two subgroups. All animals underwent brain trauma. The groups were as follow: 1) trauma, 2) melatonin receptor antagonist vehicle + estrogen, 3) MT1 melatonin receptor antagonist + estrogen, 4) MT2 melatonin receptor antagonist+ estrogen, 5) MT3 melatonin receptor antagonist+ estrogen. Brain edema (24 hr), intracranial pressure (ICP) (-1, 0, 1, 4 and 24 hr) and blood–brain barrier (BBB) permeability (5 hr) and aquaporin (AQP4) expression (24 hr) were evaluated after TBI. Results: MT1, MT2 and MT3 melatonin receptors had anti-edema effects while MT1 and MT2 have a role in protecting BBB by estrogen. Furthermore, the activity of MT3 and MT2 melatonin receptors weakened the effect of estrogen on ICP. However, melatonin receptors had no role in the effect of estrogen on AQP4 protein. Conclusion: Based on the above results, it seems that melatonin receptors appear to influence the effect of estrogen in TBI without altering AQP4 expression. The role of the receptors is different in this interaction.