Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes stroke patients to PIDs as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome. Display omitted •Sensory stimuli, episodic hypoxia, or hypotension trigger peri-infarct depolarizations•Mechanism involves transient worsening in O2 supply-demand mismatch in penumbra•In light of the data, clinical management of brain injury may need to be revisited Peri-infarct depolarizations (PIDs) worsen tissue outcome in stroke. Von Bornstädt et al. show that somatosensory activation, and episodic hypoxemia or hypotension all trigger PIDs by worsening the oxygen supply-demand mismatch. Therefore, minimizing sensory stimulation and hypoxic or hypotensive transients may be beneficial in acute brain injury.