Esketamine, a derivative of the anesthetic ketamine, prevented postoperative cognitive dysfunction in aged mice by activating the SIRT3/AMPK/mTOR cellular pathway. The treatment improved spatial memory performance, reduced neuroinflammation, enhanced mitochondrial function, and prevented harmful microglial activation in brain tissue following surgical stress. This finding illuminates a critical vulnerability in aging brains during medical procedures. Postoperative cognitive dysfunction affects up to 40% of elderly surgical patients, potentially accelerating dementia progression and reducing quality of life. The SIRT3/AMPK/mTOR pathway represents a master regulator of cellular energy metabolism and longevity signaling, making it an attractive therapeutic target. However, this preclinical mouse study has significant limitations. The surgical model may not fully replicate human operative stress, and esketamine's psychoactive properties complicate clinical translation. The cognitive benefits observed here could reflect the drug's known rapid antidepressant effects rather than neuroprotection specifically. While promising for understanding perioperative brain vulnerability, human trials will need to carefully balance cognitive protection against psychiatric side effects in elderly populations already at risk for delirium and confusion.