Aim: For colonoscopy patients, we compared the safety and efficacy of the propofol and fentanyl (PF) and the combination of dexmedetomidine and ketamine (DK) for sedation. Method: Sixty patients undergoing colonoscopy were randomized into two groups for the purposes of anesthesia in this study: group A received PF, and group B received DK. 30 patients comprised the PF group, while the remaining thirty patients comprised the DK group. Both groups exhibited comparable demographic characteristics. At 2, 5, 10, and 15 minutes, the sedation score (as determined by the Ramsy scale) and vital signs of the patients were documented. A protocol was utilized to document complications such as apnea, hypotension, hypoxia, nausea, and vomiting, in addition to the satisfaction of the gastroenterologist. The data were analyzed with SPSS V.18 and a significance level of ˂0.05 using chi-square, independent t-tests, and repeated measure analysis. Result: The mean score of sedation was3.78  ± 0.41 in DK group and4.15  ± 0.37 in PF group (p value = 0.002). Serious complications, including hypotension (p value = 0.004) and apnea (p value = 0.20) were significantly higher in PF group. Conclusion: Compared to PF, the combination of DK and PF provides adequate sedation with fewer complications in patients undergoing colonoscopy.