Accumulating studies have unraveled that dexmedetomidine (DEX) is neuroprotective against brain damage. However, it remains largely unknown about the mechanism involved in the neuroprotective effect of DEX. Therefore, this study explored whether DEX could affect mitophagy and pyroptosis in hypoxic-ischemic brain damage. We established a hippocampal neuron model of oxygen glucose-deprivation (OGD) and a rat model of cerebral ischemia/reperfusion (I/R) injury, which were then intervened with DEX and the autophagy inhibitor (3-MA). It was found that DEX intervention significantly increased neuron viability and mitophagy. Additionally, DEX intervention reversed increased oxidative stress and pyroptosis caused by OGD. DEX intervention further maintained the activation of the PINK1/Parkin pathway, while 3-MA treatment partly counteracted the protective effect of DEX on OGD-induced hippocampal neurons, suggesting that the inhibition of the PINK1/Parkin pathway reversed the function of DEX to increase cell viability and mitophagy and inhibit oxidative stress, pyroptosis, and apoptosis. Animal experiments also revealed that DEX intervention induced PINK1/Parkin pathway activation, reduced cerebral infarction and mitochondrial damage, promoted mitophagy, and inhibited pyroptosis, which was nullified by 3-MA treatment. Conclusively, DEX protects against pyroptosis and activates mitophagy in OGD/R-induced brain damage by activating the PINK1/Parkin pathway.