To assess the effect of subanesthetic dose of esketamine in combination with propofol on the incidence of postoperative fatigue syndrome (POFS) in patients who underwent gastroenterological endoscopy under anaesthesia. Clinical data of 160 patients who underwent gastroenterological endoscopy under anaesthesia in Huzhou Maternity & Child Health Care Hospital from January to December 2022, ASA Grade- I and II, were retrospectively selected. According to the records, patients were grouped based on the administered anesthetic. Patients who received 0.2 mg/kg of esketamine and 2~2.5mg/kg of propofol comprised Group-E, and patients who were administered one μg/kg of fentanyl and 2 - 2.5mg/kg of propofol comprised Group-F. Mean arterial pressure (MAP), oxygen saturation (SpO2) and heart rate (HR) were recorded before the operation (T0), after anesthesia (T1), three minutes after the gastroscope was inserted (T2), five minutes after the colonoscope was inserted (T3) and at the end of the operation (T4). Operating time, recovery time, propofol dosage and incidence of adverse reactions in the two groups were recorded. The Christensen scores and the incidence of POFS of all patients on Day-I before operation and 1st, 3rd, and 5th days after the operation were recorded. Compared with T0, MAP, SpO2 and HR in both groups of patients decreased at T1, T2, T3 and T4 (P<0.05). MAP, SpO2 and HR of patients in Group-E were significantly higher compared to Group-F at T1, T2, T3 and T4 (P<0.05). Compared with Group-F, the recovery time, intraoperative bradycardia and respiratory depression in Group-E were significantly lower (P<0.05), and Christensen scores and the incidence of POFS decreased significantly on the 1st, 3rd, and 5th day after the operation (P<0.05). Subanesthetic dose of esketamine combined with propofol can reduce POFS and postoperative adverse reactions in patients undergoing gastroenterological endoscopy.