Spreading depolarizations (SD) are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply-demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure (ICP) are also prevalent in injured brain. Here, using a mouse model of large hemispheric ischemic stroke, we show that mild and brief ICP elevations (20 or 30 mmHg for just 3 minutes) potently trigger SDs in ischemic penumbra (4-fold increase in SD occurrence). We also show that 30 mmHg ICP spikes as brief as 30 seconds are equally effective. In contrast, sustained ICP elevations to the same level for 30 minutes do not significantly increase the SD rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger an SD. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the ICP spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply-demand mismatch. These hemodynamic changes during ICP spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, higher rate of ICP spikes was associated with SD clusters in a retrospective series of patients with aneurysmal subarachnoid hemorrhage with strong temporal correspondence. Altogether, our data show that ICP spikes, even when mild and brief, are capable of triggering SDs. Aggressive prevention of ICP spikes may help reduce SD occurrence and improve outcomes after brain injury.