Mild traumatic brain injuries (mTBI) affect millions of people globally every year. The clinical presentation of this injury is highly variable, and its progression from the acute to chronic stages of injury is driven by a dynamic pathophysiology. More specifically, biomechanical brain damage can trigger complex cellular, molecular, functional, genetic, and metabolomic changes. Recent research has taken aim at understanding the association between such complex changes and clinical outcomes, with the ultimate intent of identifying prognostic indicators. This is important as to date, current diagnostic protocols using patient reported symptom tracking and routine medical imaging are limited, often subjective, and can lead to missed diagnoses. Thus, neither patients nor their physicians can currently predict recovery timeline and whether recovery will be complete. Consequently, biological markers need to be determined that can improve diagnostic and recovery assessments following brain injuries. Possible indicator candidates, based on human and animal research, include the expression of neuroprotective genes and microRNAs (i.e., GFAP, BDNF, MBP) and single nucleotide polymorphisms (i.e., BDNF, COMT, APOE, D2R2). However, these factors are non-specific in terms of injury location and severity. Due to the vast range of physiological, molecular and omics alterations present post-mTBI, it is clear that mTBIs are a highly complex pathophysiological clinical problem. Thus, the purpose of this review is to provide a comprehensive understanding of post-mTBI genetic and metabolic brain changes, both at the cellular and molecular level, to understand how they can affect the symptoms and outcome of mTBIs. We discuss how these changes may be leveraged for improved acute detection of brain injury, and their potential for use in future personalized treatments.