Objective To evaluate the effect of different doses of esketamine combined with propofol medium and long chain fat emulsion in painless gastroenteroscopy.Methods 144 patients who were scheduled to receive painless gastroenteroscopy from January 2022 to December 2023 were randomly divided into four groups with 36 cases in each group. The load dose of esketamine in group A, group B and group C was 0.2, 0.3 and 0.4 mg/kg respectively, and group D was treated with equivalent normal saline instead of esketamine as the control. All the patients were administrated with propofol medium and long chain fat emulsion during the examination. Heart rate (HR), mean arterial pressure (MAP) and percutaneous arterial oxygen saturation (SpO₂) were recorded immediately after electrocardiograph monitoring was established (T₀), immediately before examination (T₁), immediately after gastroscopy placement (T₂), immediately before colonoscopy (T₃), immediately after colonoscopy implantation (T₄) and immediately after examination (T₅). The dosage of propofol medium and long chain fat emulsion, recovery time and discharge time were compared among the four groups. Patients were assessed with quality of recovery-40 questionnaire (QoR-40) at T₀ and at wake time (T₆). The adverse reactions of the four groups were compared.Results There were statistically significant differences in the temporal effects of HR, MAP and SpO₂ among the 4 groups (F = 3.91, 21.65, 6.17, P < 0.05); There were statistically significant differences in the intergroup effects of HR, MAP and SpO₂ among the 4 groups (F = 14.57, 7.14, 30.34, P < 0.05). The variation trend of SpO₂ in groups A, B, C and D was statistically significant (F = 2.88, P < 0.05). The first and total dosage of propofol medium and long chain fat emulsion, and the recovery time of the four groups were statistically significant (P < 0.05). The initial dosage and total dosage of propofol medium and long chain fat emulsion in group A, group B and group C were significantly lower than those in group D (P < 0.05), and group B and group C were significantly lower than group A (P < 0.05), but there was no significant difference between group B and group C (P > 0.05). The recovery time of group A and group B were significantly shorter than that of group C and group D (P < 0.05), and group C was significantly longer than that of group D (P < 0.05), and there was no significant difference between group A and group B (P > 0.05). There was no significant difference in the time of get discharged from the hospital among the four groups (P > 0.05). The total scores of QoR-40 in four group at T₆ were significantly lower than those at T₀ respectively (P < 0.05). T₆ QoR-40 total score: group B was significantly higher than group A, Group C and group D (P < 0.05), group A and group C were significantly higher than group D (P < 0.05), and there was no significant difference between group A and group C (P > 0.05). There were significant differences in the incidence of hypoxemia, hypotension, bradycardia, tachycardia, body movement and dizziness among the four groups (P < 0.05). The incidence of hypoxemia, hypotension and bradycardia in group B and group C was significantly lower than that in group D (P < 0.083), and the incidence of dizziness in group C was significantly higher than that in group D (P < 0.0083). Among them, 1 case in group A and 3 cases in group D needed mask pressure ventilation due to hypoxemia. There was no significant difference in the incidence of nausea and vomiting among the four groups (P > 0.05).Conclusion During painless gastroenteroscopy, the application of 0.3 mg/kg esketamine combined with propofol medium and long chain fat emulsion can help maintain the hemodynamic stability, alleviate the respiratory and circulatory inhibition caused by propofol medium and long chain fat emulsion, accelerate recovery, and reduce adverse reactions in patients.