Objective To observe the sedative effect and safety of esketamine hydrochloride combined with dexmedetomidine in patients with difficult airway undergoing awake nasotracheal intubation. Methods A total of 40 patients with difficult airway who were scheduled for surgery under general anesthesia and required conscious endotracheal intubation were enrolled. According to the random number table method, they were divided into two groups (n=20): a sufentanil‑dexmedetomidine group (group F) and an esketamine‑dexmedetomidine group (group S). Both groups were intravenously infused with dexmedetomidine at a loading dose of 1 μg/kg over 10 min. Then, group F was intravenously injected with 0.1 μg/kg sufentanil twice, while group S was intravenously injected with 0.1 mg/kg esketamine hydrochloride twice. Their heart rate, mean arterial pressure (MAP), respiratory rate (RR), pulse oxygen saturation (SpO2), Ramsay sedation score were recorded when entry into the operation room for 5 min (T0), the first bronchoscopy insertion (T1), the second bronchoscopy insertion (T2), the third bronchoscopy insertion (T3), immediately after intubation (T4), and 1 min after intubation (T5). Their intubation at T1 to T5 (including choking, intubation comfort and tolerance after intubation) were observed. Furthermore, respiratory depression and hypoxemia during intubation, the first PETCO2 after successful connection to the ventilator, and the follow‑up visit 24 h after surgery (memory, adverse reactions and patient satisfaction towares intubation) were observed. Results Compared with those at T0, group F showed decreases in heart rate at T1 and T2, decreases in MAP at T1 and T3‒T5, decreases in RR at T2‒T5, decreases in SpO2 at T1‒T5, and remarkable increases in Ramsay sedation scores at T1‒T5 (P<0.05), while group S presented decreases in RR at T1‒T2, decreases in SpO2 at T1‒T5, and increases in Ramsay sedation score at T1‒T5 (P<0.05). Compared with those at T1, group F showed decreases in RR at T2‒T5, decreases in SpO2 at T3‒T5, and increases in Ramsay sedation scores at T2‒T5 (P<0.05), while group S presented increases in Ramsay sedation score at T2‒T5 (P<0.05). Compared with those at T2, the Ramsay sedation score increased in group F at T3‒T5 (P<0.05), and significantly increased in group S at T2‒T5 (P<0.05). Compared with group F, group S presented increases in MAP at T1, T3, and T4, increases in RR at T4 and T5, and increases in SpO2 at T3‒T4, decreases in the incidence of respiratory depression and remarkable decreases in the first PETCO2 after successful connection to the ventilator (P<0.05). There was no significant difference in the incidence of choking, intubation comfort and tolerance after intubation between the two groups at T1‒T5 (P>0.05). There was no significant difference in the incidence of hypoxemia between the two groups (P>0.05). There was no statistical difference in post‑operative 24 h memory, adverse reactions and satisfaction towards intubation between the two groups (P>0.05). Conclusions Esketamine hydrochloride or sufentanil combined with dexmedetomidine can provide effective sedation for patients with difficult airway through awake nasotracheal intubation, but esketamine hydrochloride combined with dexmedetomidine results in a low incidence of respiratory depression during fiberoptic bronchoscope guided awake nasotracheal intubation, with better safety.