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Background: Endoscopy provides valuable diagnostic information and intervention therapies for gastroenterologists. Therefore, various drugs have been used to induce sedation in patients undergoing endoscopy, whereas none have been considered preferred by endoscopists. In the current study, we decided to use the combination of magnesium sulfate, ketamine, and their synergistic effects for creating partial analgesia to increase the satisfaction of endoscopists and patients. Methods: This study is a Double-Blind Randomized Clinical Trial that investigates the sedative effect of ketamine, magnesium sulfate, and propofol in endoscopy. Patients were selected from individuals over 12 years old and with American Society of Anesthesia (ASA) physical status I or II. The study was performed on 210 patients classified as ASA (I have no underlying disease) or II (with underlying controlled disease). The whole group was relieved of pain through sedation according to Ramsay criteria, satisfaction with the operation, duration, recovery, nausea and vomiting, hypotension, and decreased oxygen saturation were compared. Results: A total of 155 patients were enrolled in our study, including 51 patients (midazolam and propofol), 55 patients (midazolam and ketamine), and 49 patients (midazolam and ketamine and magnesium). The results showed that preoperative heart rate, intraoperative systolic blood pressure, intraoperative diastolic blood pressure, postoperative heart rate, postoperative systolic blood pressure, and postoperative heart rate were significantly different between the groups. Conclusion: The satisfaction of the endoscopic was achieved to a great extent, mainly in the group receiving midazolam and propofol and in the group receiving midazolam and ketamine. In most cases, the satisfaction of the endoscopic was acceptable, and the low satisfaction of the endoscopic was more in the group receiving midazolam. Ketamine and magnesium were observed. The two compounds midazolam-ketamine, and midazolam-propofol, have a more favorable effect than the combination of midazolam, ketamine, and magnesium.