Objective To evaluate the application of moderate sedation in obese patients during painless gastroscopy. Methods A total of 120 obese patients who underwent painless gastroscopy from April 2020 to April 2023 were selected. According to the random number table method, they were divided into two groups (n=60): an observation group and a control group. Moderate sedation was conducted in the observation group, while general anesthesia was performed in the control group. Their pulse oxygen saturation (SpO2) and mean arterial pressure (MAP) were recorded before anesthesia (T0), at the end of drug administration (T1), when the gastroscope passed through the throat (T2), and at the end of gastroscopy (T3). The time of gastroscopy, the time of awakening from anesthesia, the time to discharge, the amount of propofol, and the score of cardia exposure during gastroscopy were recorded in both groups. Furthermore, the scores of patient comfort, patient satisfaction, and physician satisfaction within 24 h after gastroscopy were also collected. The incidences of adverse reactions during the examination and after awakening were recorded. Results For the observation group, SpO2 at T1 and T2 was higher than that in the control group (all P<0.05), while MAP at T1, T2, and T3 was higher than that in the control group (all P<0.05). In the control group, SpO2 at T1 and T2 was lower than that at T0 (all P<0.05), and MAP at T1, T2, T3 was lower than that at T0 (all P<0.05). In the observation group, MAP at T1 and T2 was lower than that at T0 (all P<0.05). The observation group showed decreases in the time of awakening from anesthesia and the amount of propofol (all P<0.05), increases in the percentage of 4 points of cardia exposure (P<0.05), and decreases in the incidence of hypoxia and hypotension, compared with the control group (all P<0.05). There was no statistical differences in other indicators (all P>0.05). Conclusions Compared with general anesthesia, moderate sedation for painless gastroscopy in obese patients can effectively relieve the impact on respiratory and circulatory function, improve the safety of painless gastroscopy. The degree of cardia exposure is better, the incidence of hypoxia and hypotension is lower, and the patient comfort, satisfaction, and physician satisfaction are higher.