Background This study compared dexmedetomidine versus ketamine as regard sedation and anxiolysis produced by giving them through intranasal route to pediatric patients undergoing adenotonsillectomy. This study was double-blinded randomized comparative prospective interventional clinical study done in Ain Shams University Hospital (El Demerdash Hospital) on 76 pediatric patients who underwent adenotonsillectomy, and they were randomly allocated equally into two main groups; group D received 2 μg/kg intranasal dexmedetomidine and group K received 5 μg/Kg intranasal ketamine 30 min before the operation, and the aim of this study was to compare the efficacy of intranasal dexmedetomidine versus intranasal ketamine for anxiolysis and sedation to alleviate stress, agitation, and anxiety in children before general anesthesia and for promoting good level of sedation for them. Results Results of this study as regards sedation level that was assessed by modified Ramsay sedation score showed that there was statistically significant difference between both groups at 10, 20, and 30 min from intranasal application of the drug (P value < 0.05), the median (IQR) of sedation score at 10, 20, and 30 min preoperative in group D was (2 (2 – 2)), (3 (3 – 4)), (4 (4 – 5)) compared to (2 (2 – 3)), (3 (2 – 3)), (4 (3 – 4)) in group K respectively which revealed that there was better and effective sedation in group D more than in group K, this difference was statistically significant but clinically insignificant as both drugs produced an acceptable level of sedation and decreased the level of anxiety in children. Conclusion Both drugs produce effective and favorable sedation level with superiority to dexmedetomidine in sedation scores and time of onset of sedation, and also there was little decrease in heart rate and mean arterial pressure which is favorable during such surgeries; also, there was accepted level of cannulation and parental separation scores, and the parents were highly satisfied with the procedure and were grateful for us due to alleviating stress and anxiety from them and from their children.