ATP-sensitive potassium channel (KATP) is a kind of inwardly rectifying potassium channel that suppresses depolarization in both cell membrane and mitochondria, and has an important role to make and keep resting membrane potential. It is known that activation of KATP protected the cells from ischemic damage in heart and brain. However, the underlying mechanism is not clear. Here, we have investigated that how minoxidil suppresses ischemic damage and excitotoxicity. Transient ischemia model mice were prepared by 1-h middle cerebral artery occlusion using 6-week old male C57/BL mice. Injection of minoxidil immediately after the operation prevented the damage in a concentration-dependent manner. N-methyl-D-aspartic acid (NMDA) induced mitochondrial depolarization after the increase in calcium influx into the cells. Increasing mitochondrial depolarization correlated to extent of neuronal degeneration, while pre-treatment of minoxidil inhibited it. Therefore, these results suggested that the decrease in intracellular potassium level may suppress the neurodegeneration via suppression of mitochondrial depolarization.