The current understanding of the pathophysiology of mild traumatic brain injury (mTBI) is, without doubt, incomplete. Nevertheless, we tried to summarize the state-of-the-art explanation of how the brain is continuously injured even after a single impact. We also reviewed the real struggle of diagnosing mTBI, which culminated in showing the potential of blood-based biomarkers as an alternative or complementary way to overcome this difficulty. Pathophysiology of mTBI is subdivided into primary and secondary injuries. Primary injury is caused by a direct impact on the head and brain. Secondary injury refers to the changes in energy metabolism and protein synthesis/degradation resulting from the biochemical cascades as follows; calcium influx, mitochondrial dysfunction, fractured microtubules, and Wallerian degeneration, neuroinflammation, and toxic proteinopathy. Since the diagnosis of mTBI is made through the initial clinical information, it is difficult and inaccurate to diagnose mTBI without the absence of a witness or sign of head trauma. Blood-based biomarkers are expected to play an important role in diagnosing mTBI and predicting functional outcomes, due to their feasibility and the recent progress of targeted proteomics techniques (i.e., liquid chromatography tandem mass spectrometry [LC-MS/MS]).