BackgroundAnticholinergic drugs are commonly used as premedication in clinical practice. The effects of premedication of atropine, penehyclidine, and glycopyrrolate on postoperative delirium in older patients remain unclear.ObjectiveThe aim of this study was to observe the effects of premedication with atropine, penehyclidine, and glycopyrrolate on postoperative delirium (POD) in older patients undergoing endoscopic gastric or esophageal submucosal dissection.MethodsOlder patients undergoing endoscopic gastric or esophageal submucosal dissection were randomly divided into atropine group (A group), glycopyrrolate group (G group), penehyclidine group (P group), and normal saline group (NS group), with 144 cases in each group. The primary outcome was the incidence of POD 24 h after surgery. The secondary outcomes were the incidence of POD 48 h and 72 h after surgery, perioperative saliva secretion levels, RASS scores, QoR-15 scores, VAS scores of dry mouth, postoperative nausea VAS scores, and severity of postoperative vomiting.ResultsThe incidence of POD 24 h after surgery was significantly higher in the A (20.1%) and P (23.6%) groups than in the NS group (9%) (95% CI, 0.030–0.191, p = 0.006, and 95% CI, 0.062–0.229, p = 0.001, respectively), and the incidence of POD between the NS group (9.0%) and G group (10.4%) was comparable (95% CI, −0.054–0.082, p = 0.843). Oral saliva secretion in the A, G, and P groups at T1–T5 was significantly lower than that in the NS group (all p < 0.001). Twenty four hours after surgery, the QoR-15 score in the A group (124.0 ± 13.3) was significantly lower than that in the NS group (132.4 ± 12.1) (95% CI, −11.338 to −5.397, p < 0.001).ConclusionGlycopyrrolate is more suitable as a premedication for older patients without aggravating postoperative delirium or prolonging dry mouth.Clinical Trial Registrationhttp://www.chictr.org.cn/showproj.html?proj=212300; Registration number: ChiCTR2300078413.