This review, authored by Serena Silvestro, Ivana Raffaele, Angelo Quartarone, and Emanuela Mazzon, focuses on traumatic brain injuries (TBIs) and their biomarkers and molecular mechanisms. TBIs, which can be categorized into primary and secondary damage, are significant health issues causing long-lasting effects and disrupting daily life. The review highlights the importance of biomarkers such as neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in predicting cognitive outcomes and guiding personalized treatment strategies. In terms of pharmacological progress, the most promising approaches target neuroinflammation, oxidative stress, and apoptotic mechanisms, offering potential for reducing TBI impact and aiding neurological rehabilitation. The review also discusses the role of extracellular vesicles and novel biomarkers like beta-synuclein in understanding and treating TBIs. Additionally, it explores multifaceted therapeutic strategies, including anti-inflammatory agents, immunomodulators, antioxidant therapies, glutamate modulators, and antiferroptotic approaches, to enhance neuronal survival and neurorepair. The review emphasizes the need for further research to validate these biomarkers and therapeutic approaches in larger and more diverse samples, particularly in pediatric cases and specific contexts like sport-related concussions and military training.This review, authored by Serena Silvestro, Ivana Raffaele, Angelo Quartarone, and Emanuela Mazzon, focuses on traumatic brain injuries (TBIs) and their biomarkers and molecular mechanisms. TBIs, which can be categorized into primary and secondary damage, are significant health issues causing long-lasting effects and disrupting daily life. The review highlights the importance of biomarkers such as neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in predicting cognitive outcomes and guiding personalized treatment strategies. In terms of pharmacological progress, the most promising approaches target neuroinflammation, oxidative stress, and apoptotic mechanisms, offering potential for reducing TBI impact and aiding neurological rehabilitation. The review also discusses the role of extracellular vesicles and novel biomarkers like beta-synuclein in understanding and treating TBIs. Additionally, it explores multifaceted therapeutic strategies, including anti-inflammatory agents, immunomodulators, antioxidant therapies, glutamate modulators, and antiferroptotic approaches, to enhance neuronal survival and neurorepair. The review emphasizes the need for further research to validate these biomarkers and therapeutic approaches in larger and more diverse samples, particularly in pediatric cases and specific contexts like sport-related concussions and military training.