Diffuse axonal injury (DAI) is a common and significant pathological feature of traumatic brain injury (TBI), affecting all severities of brain trauma. DAI involves a spectrum of effects, from primary mechanical disruption of the axonal cytoskeleton to secondary physiological changes, including transport interruption, swelling, and proteolysis. These changes can manifest acutely as immediate loss of consciousness or confusion and persist as coma and cognitive dysfunction. Recent evidence suggests that TBI may induce long-term neurodegenerative processes, such as progressive axonal pathology, which can continue years after the injury. Axonal degeneration has been linked to the development of Alzheimer's disease-like pathological changes. The review discusses the current understanding of DAI as a unique mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI. The historical perspective of DAI, its pathological features, and the link between DAI and coma or transient loss of consciousness are also explored. The potential primary mechanical damage due to axonal trauma and the secondary chemical cascades following TBI are discussed, along with evidence for persistent axonal degeneration following TBI. The relationship between TBI and neurodegenerative diseases, particularly Alzheimer's disease, is highlighted. Finally, the conclusions emphasize the substantial pathological consequences of DAI due to TBI and the potential therapeutic targets for treating TBI and mitigating chronic neurodegeneration.Diffuse axonal injury (DAI) is a common and significant pathological feature of traumatic brain injury (TBI), affecting all severities of brain trauma. DAI involves a spectrum of effects, from primary mechanical disruption of the axonal cytoskeleton to secondary physiological changes, including transport interruption, swelling, and proteolysis. These changes can manifest acutely as immediate loss of consciousness or confusion and persist as coma and cognitive dysfunction. Recent evidence suggests that TBI may induce long-term neurodegenerative processes, such as progressive axonal pathology, which can continue years after the injury. Axonal degeneration has been linked to the development of Alzheimer's disease-like pathological changes. The review discusses the current understanding of DAI as a unique mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI. The historical perspective of DAI, its pathological features, and the link between DAI and coma or transient loss of consciousness are also explored. The potential primary mechanical damage due to axonal trauma and the secondary chemical cascades following TBI are discussed, along with evidence for persistent axonal degeneration following TBI. The relationship between TBI and neurodegenerative diseases, particularly Alzheimer's disease, is highlighted. Finally, the conclusions emphasize the substantial pathological consequences of DAI due to TBI and the potential therapeutic targets for treating TBI and mitigating chronic neurodegeneration.