Spreading depolarizations (SDs) are massive waves of depolarization of neurons and astrocytes, which are characterized by a massive reduction of local cortical activity that can last up to several minutes. Restoration of the homeostasis following this brain phenomenon is extremely energy-consuming, therefore it can be delayed or completely absent in already energy-deprived tissues, leading to deleterious consequences. Although related to the pathophysiology of a broad number of diseases, including hemorrhage, migraine and stroke, SDs play a particular harmful role in the context of traumatic brain injury (TBI), as they are linked to the development of secondary injury. This further evolution of already detrimental damages often results in poor clinical outcome, which strongly affects patients' quality of life, diminishing their functional independence.