Pituitary dysfunction with abnormal GH secretion and neurocognitive deficits are common consequences of traumatic brain injury (TBI). Recognizing the comorbidity of these symptoms is of clinical importance; however, efficacious treatment is currently lacking.A review of studies in PubMed published between January 1980 to March 2020 and ongoing clinical trials was conducted using the search terms "growth hormone," "traumatic brain injury," and "gut microbiome."Increasing evidence have implicated the effects of TBI in promoting an interplay of ischemia, cytotoxicity and inflammation that renders a subset of patients to develop post-injury hypopituitarism, severe fatigue, impaired cognition and behavioral processes. Recent data have suggested an association between abnormal GH secretion and altered gut microbiome in TBI patients, thus prompting the description of a hypothesized new clinical syndrome called "Brain Injury Associated Fatigue and Altered Cognition" (BIAFAC). Notably, these patients demonstrate distinct characteristics to those with GH deficiency from other non-TBI causes in that their symptom complex improves significantly with recombinant human GH treatment, but does not reverse the underlying mechanistic cause as symptoms typically recur upon treatment cessation.The reviewed data describes the importance of alterations of the GH/IGF-I axis and gut microbiome after brain injury and its influence in promoting neurocognitive and behavioral deficits in a bi-directional relationship, and highlight a new clinical syndrome that may exist in a subset of TBI patients in whom recombinant human GH therapy could significantly improve symptomatology. More studies are needed to further characterize this clinical syndrome.