ABSTRACT Background A wide range of drugs are used for sedation in gastrointestinal (GI) endoscopy procedures, including midazolam, dexmedetomidine, and ketamine. Therefore, this study aimed to compare the effects of these drugs in combination with propofol among cancer patients undergoing GI endoscopy. Methods This randomized, double-blinded study was carried out on 75 cancer patients who underwent GI endoscopy. Patients were categorized into three equal groups. Group D: received dexmedetomidine 0.5 µg/kg bolus infusion over 10 min. Group K: received ketamine 0.5 mg/kg. Group M: received midazolam 0.05 mg/kg. With these drugs, 0.5 mg/kg propofol was administered intravenously with incremental 20 mg till achievement of Ramsey sedation score (RSS) 3–4. After that, 0.5 mg/kg propofol boluses were offered for rescue sedation. Results The endoscopy duration was comparable in the three groups. Time of RSS 3–4 achievement and total propofol dose (P < 0.05) were significantly lower in group D and group K compared to group M. Time to eye-opening were significantly lower in groups D, and K compared to group M, with insignificant difference between group K and group D. Moreover, the heart rate (HR) and mean arterial pressure (MAP) of group K at 10 min, 15 min, 20 min, 25 min, and 30 min, and PACU were significantly greater than D and M groups (P < 0.05). Incidence of hypotension and bradycardia were comparable in the three groups. Conclusions In cancer patients who underwent GI endoscopy, dexmedetomidine-propofol and ketamine-propofol had better sedation efficacy [lower achievement time of RSS 3–4, total propofol dose, and eye-opening time] compared to midazolam-propofol group with superior sedative effect of ketamine-propofol than dexmedetomidine-propofol. While ketamine-propofol had more stable HR and MAP.