Background: In order to assess the effectiveness of various analgesio-sedative combinations for pain relief and sedation in pediatric dental patients, a thorough evaluation of clinical studies and patient outcomes is necessary. Methods: A total of 128 healthy, uncooperative pediatric dental patients were randomly allocated to receive one of the four combinations of drugs via the intranasal (IN) route: Group I received midazolam-ketamine (MK), Group II received dexmedetomidine-ketamine (DK), Group III received midazolam-fentanyl (MF), and Group IV received dexmedetomidine-fentanyl (DF) in a parallel-arm study design. The efficacy and safety of the combinations were evaluated using different parameters. Results: The onset of sedation was significantly faster in the DF group than in the DK, MF, and MK groups (P < 0.001). The depth of sedation was significantly higher in the DK and DF groups than in the MK and MF groups (P < 0.01). DK and DF produced significant intra- and postoperative analgesia when compared with combinations of MK and MF. No significant adverse events were observed for any of the combinations. Conclusions The DK and DF groups showed potential as analgesio-sedatives in view of their anxiolytic and analgesic effects.