Background and aim Endoscopy procedures are generally performed under sedation, which ranging from minimal sedation to deep sedation. Conscious sedation during colonoscopic procedures provides a high level of patient and physician satisfaction. An ideal sedative agent should allow rapid modification of the sedation level by modifying the dose and should not have any adverse effects. Because such an ideal sedative agent does not exist, the combination use of dexmedetomidine with opioids (fentanyl or pethidine) may have the advantages over the use of a single agent. The goal of this study was to assess the effect of dexmedetomidine in combination with fentanyl or pethidine as a sedative for outpatient colonoscopy on hemodynamics, level and onset of sedation, analgesia, and degree of satisfaction of the colonoscopist and patients. Patients and methods A total of 60 colonoscopy patients between 21 and 60 years of age were included in the study. The patients scheduled for elective outpatient colonoscopy (with conscious sedation) were randomized into two groups: group 1 ‘DF group’ (N=30): dexmedetomidine 1 μ/kg/h infusion by syringe pump along with 1 μ/kg fentanyl was administered before the start of colonoscopy as a single shot, and Group 2 ‘DP group’ (N=30): dexmedetomidine 1 μ/kg/h infusion by syringe pump along with 1 mg/kg pethidine was administered before the start of colonoscopy as a single shot. The assessment includes heart rate (HR, beats/min), mean arterial blood pressure (MAP, mmHg), oxygen saturation at baseline and every 5 min, onset and level of sedation by Ramsay Sedation Score (RSS) after administration of the drugs, Numeric Pain Rating Scale at the end of colonoscopy, and the degree of satisfaction of the patients and the colonoscopist. Results The average value of the 6 h measurements in fentanyl group was 75.6±0.91 beats/min; whereas in pethidine group was 92.2±0.67 beats/min, with highly significant statistical difference (P<0.001), whereas there were nonsignificant differences regarding MAP and oxygen saturation. There was a highly significant decrease in the onset of sedation and increase in RSS and Numeric Pain Rating Scale in fentanyl group compared with pethidine group (P<0.01 for all). Moreover, there were nonsignificant differences regarding the degree of satisfaction for the colonoscopist and the patient (P>0.05). Multiple regression analysis shows that the increase in baseline HR had an independent effect on increasing onset of sedation (P<0.0001). Moreover, the fentanyl usage and the decrease in baseline HR had an independent effect on increasing RSS (P<0.01). Conclusion Patients who underwent colonoscopy and received dexmedetomidine-fentanyl regimen showed better hemodynamics (decreased HR, normal MAP, and oxygen saturation measurements), along with rapid onset of sedation and satisfied RSS compared with patients who received dexmedetomidine–pethidine regimen. In contrast, pethidine group showed better analgesia than fentanyl group. Both groups showed comparable satisfaction results in the colonoscopist and patients.