Traumatic brain injury (TBI) is a serious health concern, yet there is a lack of standardized treatment to combat its long-lasting effects. The objective of the present study was to provide an overview of the limitation of conventional stem-cell therapy in the treatment of TBI and to discuss the application of novel acellular therapies and their advanced strategies to enhance the efficacy of stem cells derived therapies in the light of published study data. Moreover, we also discussed the factor to optimize the therapeutic efficiency of stem cell-derived acellular therapy by overcoming the challenges for its clinical translation. Hence, we concluded that acellular therapy possesses the potential to bring a breakthrough in the field of regenerative medicine to treat TBI.