Traumatic brain injury (TBI) is the leading cause of death and disability in young and adult people. Since TBI is a lesion characterized by its heterogeneity and complexity, many clinical and pharmacological approaches have been unsuccessful. The current understanding of the physiopathology of TBI indicates that it is imperative to focus on a multifactorial therapy. Endogenous hormones have pleiotropic neuroprotective effects that can be used for a therapeutic approach in TBI. However, these neurosteroids have secondary effects depending on the target tissue. In this concern, the development of more specific estrogenic-progestogenic-androgenic like compounds and the advances in elucidating their protective role in TBI has led to the use of SERMs and STEARs. In vitro and in vivo models have shown promising results in elucidating the role of neurosteroids and how they may be considered as a potential therapy aimed at improving the outcome in TBI.