Introduction: Traumatic brain injury (TBI) is one of the leading causes of death of men under the age of 35 that mostly occurs during the road accidents. Current clinical treatments cannot prevent the secondary brain damage induced by cytotoxicity. Progesterone, as a primary sex hormone, is a neuroprotective compound in TBI and stroke. Indeed, progesterone increases anti-oxidant activities, decreases inflammatory factors, and reduces the expression of inflammatory cytokine, which can prevent secondary brain injury and edema. Conclusion: This review focused on the preventive effect of progesterone on secondary brain injury and edema by modulation of inflammatory factors in TBI. Although, the exact mechanism of TBI has not been discovered, studies suggest that this hormone can be a safe treatment for TBI and other neurodegenerative diseases.