Background <p>Postoperative delirium (POD) is a frequent and serious complication in older patients undergoing orthopedic surgery. This study aimed to compare the effects of midazolam and dexmedetomidine on the incidence of POD in elderly patients undergoing total knee arthroplasty under spinal anesthesia.</p> Methods <p>In this prospective, double-blind, randomized, parallel group comparative trial, a total of 175 patients aged 65&#xa0;years or older were allocated to receive either midazolam or dexmedetomidine for intraoperative sedation. The primary outcome was the incidence of POD, evaluated using the confusion assessment method for five postoperative days. Secondary outcomes included the quality of sedation, incidence of sedation failure, postoperative analgesic profiles, and complication rates.</p> Results <p>The incidence of POD was significantly lower in the dexmedetomidine group compared to the midazolam group (13.9% vs. 27.4%, <i>P</i> = 0.045). In addition, dexmedetomidine was associated with superior sedation quality and a significantly lower rate of sedation failure (<i>P</i> = 0.007 and <i>P</i> = 0.018, respectively). Postoperative pain intensity and complication rates were comparable between the two groups.</p> Conclusion <p>Dexmedetomidine significantly reduced the incidence of POD and improved sedation quality compared to midazolam. These findings suggest that dexmedetomidine may be a preferable sedative for elderly patients undergoing total knee arthroplasty under spinal anesthesia.</p> Trial registration <p>This study was registered with the WHO International Clinical Trials Registry Platform (Trial number: KCT0006587, Registration date: 16th September 2021).</p>