Injury depolarizations akin to spreading depression of Leão are important in the progression of tissue damage in ischemic stroke, intracranial hemorrhage, and trauma. Much of the research on injury depolarizations has been focused on their origins, electrophysiological mechanisms, and metabolic impact. Recent studies showed that injury depolarizations cause vasoconstriction and diminish perfusion, which radically differs from the predominantly hyperemic response to spreading depression in otherwise-normal brain tissue. This adverse hemodynamic effect exacerbates metabolic supply-demand mismatch and worsens the tissue outcome. Although the mechanisms transforming the hemodynamic response from vasodilation into vasoconstriction are unclear, recent data suggest a role for elevated extracellular K+ and reduced intravascular perfusion pressure, among other factors. Clues from physiological and pharmacological studies in normal or injured brain in different species suggest that the intense pandepolarization evokes multiple opposing vasomotor mechanisms with variable magnitudes and timing, providing a conceptual framework to dissect the complex neurovascular coupling in brain injury.