One hundred fifty-nine elderly patients undergoing lumbar spine surgery were randomized to receive esketamine plus dexmedetomidine (ED group, n=53), esketamine alone (E group, n=53), or dexmedetomidine alone (D group, n=53). The primary outcome was the incidence of postoperative cognitive dysfunction (POCD) on the first postoperative day. Secondary outcomes included POCD on the third day, serum neuron-specific enolase (NSE) and S100β levels, VAS pain scores at 2, 24, and 48 hours, and adverse events. Outcomes were assessed preoperatively and on postoperative days 1 and 3. Overall, the combination therapy significantly reduced POCD on day one, and lowered serum NSE and S100β levels compared to both monotherapies. These findings suggest that the esketamine–dexmedetomidine combination may offer neuroprotective effects and enhance postoperative recovery in elderly patients.