Objective To observe the effect of intravenous injections of sub ⁃ dose esketamine combined with midazolam before anesthesia induction on postoperative delirium （POD）in elderly patients receiving hip replacement. To explore the role of ESKE combined with MI in glutamate ⁃ induced HT22 cell injury. Methods 120 patients older than 65 who had undergone hip replacement were randomly assigned to group C，MI，ESKE or ESKE plus MI，30 for each group. 10 minutes before anesthesia，group MI received intravenous midazolam of 0.02 mg/kg，group ESKE received esketamine of 0.2 mg/kg，group ESKE plus MI received esketamine combined with midazolam，while group C received saline. The incidence of POD within 72 hours was observed. HT22 cells were divided into groups NC，G，MIC，ESKEC and ESKEC plus MIC. CCK8 was detected in each group following treatments based on relevant design. Rates of apoptosis and necrosis were measured by flow cytometry. Results The general data and hemodynamic index in the patients were not statistically significant（P > 0.05）. The inci⁃ dence of POD was lower in group ESKE plus MI than in group C，while glutamate level was higher in group POD than in group NPOD（P < 0.05）. The OD value and rates of necrosis and apoptosis in group NC，as compared with group C，were statistically significant（P < 0.05）. The OD value was greater in groups ESKEC and ESKEC plus MIC than in group G（P < 0.05）. The rates of apoptosis and necrosis were higher in group G than in groups ESKEC and ESKEC plus MIC（P < 0.05）. Conclusions Uses of sub ⁃dose esketamine combined with midazolam before anesthesia can reduce the incidence of POD in elderly patients undergoing hip replacement. ESKE combined with MI can relieve the apoptosis and necrosis of HT22 cells induced by glutamate，whose mechanism may be related to the decline in the incidence of POD.