Using an ischemic stroke rat model by applying permanent middle cerebral artery occlusion (pMCAo), we have previously demonstrated that protection of the ischemic territory can be achieved by providing intermittent sensory stimulation within a period of 2 h following the occlusion. Beyond this period, sensory stimulation becomes deleterious and results in infarct. We have further demonstrated that such sensory-based protection depends on the integrative role of activated synapses, activated neurons, activated astrocytes, and activated blood vessels. By using the same rat pMCAo model for the current study, we hypothesized that all such activations are potentially triggered by sensory stimulation-based evoked neuronal activity within the ischemic cortex, that in turn triggers the various activations that lead to protection. To test this hypothesis, we used functional imaging and postmortem histology and selectively blocked spontaneous or evoked neuronal activity within the ischemic territory by local administration of lidocaine. Our findings demonstrate that the ischemic cortex is extremely sensitive, as clear functional blockage at the site of lidocaine diffusion and a corresponding infarct at the same location were found for both spontaneous activity and sensory-based evoked activity. Furthermore, the extreme sensitivity of the ischemic cortex is demonstrated by the detrimental effects of phosphate buffer saline (PBS) application if protective sensory-based stimulation is not present following pMCAo. We conclude that neuronal activity, either spontaneous or evoked, within the ischemic cortex is pivotal for protection during the early hyperacute phase of ischemic stroke.