Severe traumatic brain injury (TBI) is a major public health issue, responsible for high rates of long-term disability and mortality. Although severe TBI is a leading cause of death worldwide, even mild head injuries can adversely impact the functional outcome. It is well described that trauma produces a complex stress response to reestablishing homeostasis. The activation of the stress response (i.e., the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system) leads to the release of glucocorticoids and catecholamines. Although fundamental for survival, the stress response is one of the major players in the development of posttraumatic complications. TBI in particular leads to a fast and intense sympathetic nervous system's activation with huge liberation of both central and peripheral catecholamines, including epinephrine (Epi) and norepinephrine (NE). Since catecholamine levels increase exponentially after TBI, they have been appraised as possible prognostic biomarkers and a target for intervention in this clinical setting. Currently, there is no particular pharmacological treatment available to reduce or limit the progression of secondary brain injury after TBI. However, preliminary data on the use of β-blockers after TBI have shown promising results. A recent meta-analysis estimated an in-hospital mortality reduction of 65%, while a matched case–control study described that the exposure to a β-blocker were associated with improved functional outcome. Despite these promising and interesting results, the use of β-blockage in the acute phase of TBI remains experimental, requiring further evaluation in a well-designed multicenter randomized clinical trial.