Background The pre-operative period is a very stressful event for most of the individuals undergoing surgery especially the pediatric patients. So, relieving their pre-operative anxiety becomes an important concern for an anesthesiologist. Many anesthetic pre-medications are used to relieve this stress response. Of these pre-medications, midazolam and dexmedetomidine are effectively used as sedatives. The present study was planned to compare intranasal dexmedetomidine with intranasal midazolam as a pre-anesthetic medication in children. Forty-eight children aged 3–7 years, of either sex, weighing 13–22 kg, with American Society of Anesthesiologists (ASA) physical status 1 and undergoing elective adenotonsillectomy surgery were enrolled in this comparative prospective, double blinded, randomized clinical study. The children were divided into 2 groups: group D and group M, of 24 each. Forty-five minutes before induction of anesthesia, group D (n = 24) received intranasal dexmedetomidine at a dose of 1 μg/kg and group M (n = 24) received intranasal midazolam of 0.2 mg/kg. Results Children who were pre-medicated with dexmedetomidine had lower sedation scores, lower anxiety levels, easier child-parent separation, better mask acceptance, and lower pain scores than those who received midazolam. The incidence of emergence agitation was decreased in both groups with no significant difference. Conclusion Intranasal dexmedetomidine seems to offer some advantages compared with midazolam. Thus, it can be used effectively and safely as a pre-anesthetic medication in children undergoing any surgical procedures under general anesthesia.