Objective: To analyze the efficacy and safety of ketamine combined with remifentanil tosylate for painless gastroscopy in elderly patients. Methods: A total of 80 elderly patients who underwent painless gastroscopy in our hospital from May 2024 to May 2025 were selected prospectively, and they were divided into experimental group and control group with a random number table method, with 40 cases in each group. The control group underwent routine anesthesia induction (propofol+fentanyl) and was maintained under propofol and fentanyl anesthesia. The experimental group underwent anesthesia induction with ketamine and fentanyl, and was maintained under anesthesia with remifentanil tosylate and fentanyl. Compare the induction time, incidence of intraoperative motor response, time to reach the target of bispectral index (BIS), time to recovery of orientation, baseline values at entry (T1), 5 minutes after anesthesia (T2), at entry (T3), heart rate variability (HRV) and mean arterial pressure (MAP) at the end of the examination (T4), preoperative and postoperative levels of motilin, cerebral oxygen saturation (rSO2). Results: The induction time, BIS compliance time, and directional force recovery time of the experimental group were shorter than those of the control group. The incidence of intraoperative body movement reaction in the experimental group was 7.50% lower than that in the control group (30.00%) (P<0.05); There was no significant difference in HRV and MAP between the two groups at T1 time (P>0.05). HRV and MAP decreased in both groups at T2 and T3 time, and increased in both groups at T4 time. The experimental group was higher than the control group (P<0.05). After surgery, both groups of gastrin and rSO2 decreased, and the experimental group was higher than the control group (P<0.05). Conclusion: The combination of ketamine and remifentanil tosylate has a significant effect on painless gastroscopy anesthesia in elderly patients. It has the advantages of short acting and controllable sedation, while improving hemodynamic stability, reducing damage to the brain and important organ function of patients, and high safety.