OBJECTIVE: Directly modulating targeted cortical function, brain stimulation provides promising techniques for stroke intervention. However, the cellular level mechanisms underlying preserved neurovascular function remains unclear. Optogenetics provides a cell-specific approach to modulate the neuronal activity. This study aims to investigate whether the exclusive excitation of sensorimotor neurons using optogenetics in an acute stroke can protect neurovascular function and reduce infarct size. METHODS: Sensorimotor neurons were transfected with channelrhodopsin-2 and excited by a 473-nm laser. The photothrombotic stroke was induced in the ipsilateral parietal cortex and the targeted area for modulation remained intact. Optogenetic stimulation was carried out within 2 h after stroke in the modulation group. Using a laser speckle contrast imaging technique, we measured the cerebral blood flow at baseline, 0, 2, and 24 h after stroke, and analyzed the hemodynamic changes in both modulation (n = 12) and control (n = 9) groups. Also, the neurovascular response was measured 24 h after stroke. RESULTS: We found that neuronal-specific excitation of an ipsilesional sensorimotor cortex at an acute stage could reduce the expansion of an ischemic area and promote the neurovascular response at 24 h after stroke. The histological and behavioral results consolidate the protective effects of optogenetic-guided neuronal modulation in acute stroke. CONCLUSION: Excitatory stimulation of ipsilesional sensorimotor neurons in an acute stroke could protect neurovascular function and reduces the expansion of ischemic area. SIGNIFICANCE: For the first time, this work demonstrates that specific neuronal modulation in the acute stroke is neuroprotective and reduces the infarct size.