The study examined 178 elderly patients (≥ 65 years) with perioperative ischemic stroke to determine whether the choice of opioid during surgery affects the risk of postoperative delirium. The overall incidence of delirium in these patients was 40.4%, with patients with delirium having significantly worse survival (30% versus 50% without delirium). The incidence of delirium was significantly lower in the fentanyl group (6.8%) compared to the sufentanil group (63.8%). In fully adjusted models, fentanyl use was associated with a significantly reduced risk of delirium (OR: 0.017, 95% CI: 0.003–0.070, p < 0.001). The lower risk of delirium with fentanyl compared with sufentanil remained consistent across subgroups stratified by age, sex, and diabetes status. The authors conclude that opioid choice may represent a modifiable risk factor that offers an opportunity to improve anesthetic management and postoperative outcomes in this high-risk population.