Spreading depression (SD) is a propagating wave of neuronal depolarization and ionic shifts, seen in stroke and migraine. In vitro, SD is associated with astrocytic [Ca²⁺] waves, but it is unclear what role they play and whether they influence cerebral blood flow, which is altered in SD. Here we show that SD in vivo is associated with [Ca²⁺] waves in astrocytes and neurons and with constriction of intracortical arterioles severe enough to result in arrest of capillary perfusion. The vasoconstriction is correlated with fast astrocytic [Ca²⁺] waves and is inhibited when they are reduced. [Ca²⁺] waves appear in neurons before astrocytes, and inhibition of astrocytic [Ca²⁺] waves does not depress SD propagation. This suggests that astrocytes do not drive SD propagation but are responsible for the hemodynamic failure seen deep in the cortex. Similar waves occur in anoxic depolarizations (AD), supporting the notion that SD and AD are related processes.