Objective The objective of this study was to evaluate the efficacy of dexmedetomidine combined with esketamine nasal spray for preoperative sedation in children undergoing tonsillectomy. Methods This prospective, randomized, double-blind study recruited 120 patients from the ages of 2 to 8 years, with American Society of Anesthesiologists (ASA) physical status classification of Ⅰ or Ⅱ and scheduled to undergo tonsil adenoidectomy. The children were randomized into three groups according to the random number table method: 2 μg/kg dexmedetomidine group (group D, n=38), 1.5mg/kg esketamine group(group S,n=38),and 1ug/kg dexmedetomidine+1mg/kg esketamine group (group DS, n=37). Intranasal medication was administered to the children in anesthesia preparations, and the primary observation was the sedation success rate; secondary outcomes included sedation onset time (time to achieve a University of Michigan Sedation Scale score of ≥2), satisfaction with intravenous cannula placement, satisfaction with parental separation, anesthesiologist satisfaction scores with induction based on a visual analog scale, time to awakening, time to stay in the PACU, number of postoperative remedial analgesics, and the occurrence of adverse events.Results The sedation success rate was significantly higher in the DS group than in the D and S groups (34/37 (91.9%) vs29/38 (76.3%) vs21/38 (55.3%); P<0.05). The median time to sedation onset in the three groups was 24.0 (20.8, 33.3), 31.0 (26.0, 40.0), and 17.0 (14.0, 20.0) minutes, respectively, and the DS group had the shortest time to reach a UMSS score of 2 (P<0.05), and the sedation onset time in the DS group was significantly shorter than that in the D (P<0.05) and S groups (P<0.05).The DS group had the highest satisfaction with intravenous cannula placement, and the incidence of adverse reactions was similar in the three groups (P>0.05). Conclusion Dexmedetomidine combined with esketamine nasal spray sedation has a higher success rate, shorter onset of sedation, and higher satisfaction with tube placement without increasing the incidence of adverse events