Objective To investigate the efficacy and safety of different doses of esketamine combined with ciprofol in patients undergoing painless gastrointestinal endoscopy. Methods A total of 240 patients, aged 18‒64 years, body mass index (BMI) of 18-30 kg/m2, American Society of Anesthesiologists (ASA) grade Ⅰ or Ⅱ, were selected for outpatient painless gastrointestinal endoscopy. Patients were divided into 4 groups according to random number table method (60 cases per group): esketamine 0.2 mg/kg group (group E1), esketamine 0.3 mg/kg group (group E2), esketamine 0.4 mg/kg group (group E3)and ciprofol single anesthesia group (group C). The groups E1, E2 and E3 were given intravenous in jection of 0.2, 0.3 mg/kg and 0.4 mg/kg esketamine, and ciprofol was given 0.2‒0.4 mg/kg after 30 s respectively, group C was given 0.4 mg/kg ciprofol intravenously. The mOAA/S≤1 min, examination time, recovery time and discharge time of 4 groups were recorded. The heart rate, pulse oxygen saturation (SpO2), mean arterial pressure (MAP), respiratory rate (RR), bispectral index (BIS) values were recorded when the patients entered the room (T0), immediately after entering the gastroscopy (T1), immediately after gastroscopy (T2), immediately after entering the endoscopy (T3), when the endoscope reached the ileocecal part (T4), at the end of the endoscopy (T5) and when awake (T6). The occurrence of adverse reactions during operation (choking,respiratory depression,hypotension, bradycardia, movement, hiccup) and after operation (giddy, nausea and vomiting, diplopia, increased secretion, nightmares) were recorded in 4 groups. The dosage of ciprofol , the number of additional cases of ciprofol , the number of additional cases of ephedrine and the supplementary analgesic drugs were recorded in 4 groups. Results Compared with group C, the time of mOAA/S≤1 min in groups E1, E2 and E3 was shorter (all P<0.05), and the time of recovery and discharge from hospital in group E3 was longer (all P<0.05). Compared with group E3, mOAA/S≤1 min, recovery time and discharge time of groups E1 and E2 were shorter (all P<0.05). Compared with group C, the dosage of ciprofol, the number of ephedrine use cases and the number of additional analgesics cases in groups E1, E2 and E3 were lower (all P<0.05), the number of additional ciprofol cases in group E2 was lower (P<0.05). Compared with group C, the incidence of cough and hypotension was lower in groups E2 and E3 (P<0.05). Compared with group E1, the incidence of intraoperative cough was lower in group E2, and the incidence of intraoperative hypotension was lower in groups E2 and E3 (all P<0.05). Compared with group E2, the incidence of coughing was higher in group E3 (P<0.05). The incidence of dizziness, increased secretion and diplopia in group E3 was higher than that in group E1, group E2 and group C (all P<0.05). Compared with T0: heart rate decreased at T4‒T5 in 4 groups (all P<0.05), MAP and BIS decreased at T1‒T5, SpO2 decreased at T1‒T2, RR decreased at T1‒T5 in group C, RR decreased at T1‒T2 in groups E1, E2 and E3; RR was increased from T3‒T5 (all P<0.05). Compared with group C: SpO2 in groups E1, E2 and E3 were higher at T1‒T2 (all P<0.05), BIS and RR in groups E1, E2 and E3 were higher at T1‒T5 (all P<0.05), and MAP in groups E1, E2, E3 were higher at T1, MAP in groups E2 and E3 were higher at T2‒T4, MAP in group E2 was higher at T5 (P<0.05). There was no significant difference in other indexes (all P>0.05). Conclusions Esketamine combined with ciprofol can be safely used in outpatient painless gastroscopy. Compared with ciprofol alone, esketamine has the advantage of reducing the inhibition of circulatory and respiratory system, and the induction dose of 0.3 mg/kg esketamine is more appropriate.