Abstract: Objective This study aimed to explore the anesthetic effect and safety of etomidate combined with different doses of nalbuphine in painless gastroscopy for the elderly patients. Methods A total of 150 elderly patients undergoing painless gastroscopy in Hubei Provincial Rehabilitation Hospital from May 2022 to May 2023 were selected as the research subjects. With the random number table method, patients were divided into group A (etomidate + 0.025 mg·kg^-1 nalbuphine) with 50 cases, group B (etomidate + 0.075 mg·kg^-1 nalbuphine) with 50 cases, and group C (etomidate + 0.05 mg · kg^-1 nalbuphine) with 50 cases. The anesthetic effects and adverse reactions of each group were compared. Results The differences in the discharge time among the three groups were statistically significant (P＜0.05), and the discharge time of group A was longer than that of groups B and C (P＜0.05). Compared with the visual analogue scale (VAS) score of patients at 5 minutes after awakening in the same group, the VAS scores at 30 minutes after awakening in all three groups decreased (P＜0.05). Compared with 2 minutes after anesthesia induction in the same group, the Ramsay sedation score (RSS) of patients at the time of endoscopic laryngeal insertion in all three groups increased (P＜0.05). Compared with the pre-anesthesia induction stage in the same group, the three groups showed statistically significant differences in heart rate (HR), oxygen saturation of blood (SpO₂), mean arterial pressure (MAP), and respiratory rate (RR) at 2 minutes after anesthesia induction, 5 minutes after anesthesia induction, and at the end of the examination (P＜ 0.05). Compared with the indicators at 2 minutes after anesthesia induction (within the same group), the three groups showed statistically significant differences in HR, SpO₂, MAP, and RR at the pre-anesthesia induction stage, as well as in MAP at the end of the examination; in addition, group A and group B each exhibited statistically significant differences in RR at 5 minutes after anesthesia induction and at the end of the examination (when compared with their own indicators at 2 minutes after anesthesia induction) (P＜0.05). Compared with 5 minutes after anesthesia induction (within the same group), the three groups showed statistically significant differences in HR, SpO₂, MAP, and RR at the pre-anesthesia induction stage, as well as in MAP at the end of the examination; group A and group B each exhibited statistically significant differences in RR at 2 minutes after anesthesia induction and at the end of the examination (when compared with their own indicators at 5 minutes after anesthesia induction) (P＜0.05). Compared with group A, there were statistically significant differences in SpO₂ at 2 minutes after anesthesia induction in group C, and in RR at 2 minutes and 5 minutes after anesthesia induction in groups B and C (P＜0.05). Compared with group B, there were statistically significant differences in SpO₂ at the end of the examination in groups A and C, in SpO₂ at 2 minutes after anesthesia induction in group C, in RR at 2 minutes and 5 minutes after anesthesia induction in group A, and in RR at 5 minutes after anethesia induction in group C (P＜0.05). Compared with group C, there were statistically significant differences in SpO₂ at 2 minutes after anesthesia induction in groups A and B, in SpO₂ at the end of the examination in group B, and in RR at 2 minutes and 5 minutes after anesthesia induction in group A (P＜0.05). After the examination, the incidences of nausea and vomiting, dizziness, body movement response and arrhythmia were compared, with those in groups B and C being lower than those in group A (P＜0.05), and the incidence of adverse reactions in group C being lower than that in group B (P＜0.05). Conclusion Etomidate combined with 0.05 mg·kg^-1 nalbuphine is more suitable for painless gastroscopy in elderly patients, being safe and effective with fewer adverse reactions.