Objective To observe the efficacy of a subanesthetic dose of esketamine combined with propofol in elderly patients undergoing painless gastrointestinal endoscopy. Methods A total of 245 elderly patients were selected for painless gastrointestinal endoscopy, they were divided into two groups according to the random number table method: fentanyl combined with propofol group (group F, 121 cases) and subanesthetic dose of esketamine combined with propofol group (group S, 124 cases). Patients in group F received intravenous fentanyl 0.8 μg/kg, while those in group S received intravenous esketamine 0.15 mg/kg, followed by propofol 1.5 mg/kg in both groups. Both groups received propofol infusion at 5 mg·kg−1·h−1 to maintain sedation. Endoscopy time, total propofol dose, awakening time, and patient satisfaction were recorded in the two groups. Heart rate, mean arterial pressure (MAP), and oxygen saturation (SpO2) at different time points (T0: before anesthesia induction; T1: 1 min after anesthesia induction; T2: the gastroscope enters the esophagus; T3: the colonoscope enters the anus; and T4: the end of endoscopic examination) were also recorded in the two groups. Adverse reactions such as hypotension, respiratory depression, bradycardia, coughing, agitation, nausea and vomiting, vertigo, and delirium were recorded in the two groups during endoscopy. Results There were no significant differences between the two groups in terms of endoscopy time, propofol dose, awakening time, and patient satisfaction (all P>0.05). At time points T1 and T2, the heart rate in group S was higher than in group F (all P<0.05). At time points T1‒T4, the MAP in group S was higher than in group F (all P<0.05). At time point T1, the SpO2 in group S was higher than in group F (all P<0.05). The incidence of hypotension, respiratory depression, and agitation in group S were lower than those in group F (all P<0.05). There was no statistical significance in other indexes (all P>0.05). Conclusions The use of a subanesthetic dose of esketamine combined with propofol in elderly patients undergoing painless gastrointestinal endoscopy results in less respiratory and circulatory depression, and minimal intraoperative agitation, which is beneficial for maintaining stable vital signs during the procedure and ensures the smooth progress of the gastrointestinal endoscopy for elderly patients.