<p>Traumatic brain injury (TBI) is a catastrophic event resulting from external mechanical forces, leading to a variety of neurological impairments. The complexity and heterogeneity of injuries are among the major speculated reasons for various unmet clinical needs in the effective management of TBI. Brain damage due to TBI results in both primary and secondary injury mechanisms. The complicated molecular pathophysiological alterations of TBI involving oxidative stress, neuroinflammation, excitotoxicity, and apoptosis emphasize the need for a greater understanding of the various signaling pathways that enable the appropriate application of multiple therapeutics for TBI management. This review delves into the multifaceted nature of TBI, involving the pathophysiology and various microenvironmental alterations that occur in TBI. In addition, different signaling pathways implicated in TBI have been elaborated in detail, including their role in TBI progression. The various potential targeting moieties that mitigate the TBI progression have been discussed. The existing clinical status of TBI therapeutics and their translational hurdles, as well as emerging advances in TBI therapy, have been comprehensively addressed.</p> Graphical abstract <p>.</p>