A combination of dexmedetomidine and ketamine for upper gastrointestinal endoscopies (UGIE) was studied in 46 children aged 2–12 years over a 6-month period. Dexmedetomidine 1 μg/kg and ketamine 2 mg/kg were given as a bolus over 5 min. Heart rate (HR), mean arterial pressure (MAP), oxygen saturation (SpO2), and sedation scores were noted before induction as baseline and then every 5 min until recovery. The duration and ease of the procedure, time to recovery, and adverse effects, if any, were also recorded. UGIE could be performed with ease in 41 of the 46 cases. The HR, MAP, and SpO2 did not change significantly from the baseline. No airway intervention was required in any patient. There was no laryngospasm or shivering in any of the children, and one, four, and 11 children had hiccup, vomiting, and increased salivation, respectively. The Pediatric Anesthesia Emergence Delirium score was <4 in all except for two cases. The results of this case series show that this drug combination not only promises to be clinically effective but also safe for UGIE in children. Further randomized controlled trials with standard sedation protocols will be required to draw definite conclusions.