Abstract: Objective To investigate the median effective dose （ED₅₀） of esketamine for inhibiting tracheal intubation response during the induction of dexmedetomidine combined with lidocaine under opioid-free anesthesia （OFA）. Methods Adult patients aged 18-59 years with body mass index （BMI）<30 kg/m² and ASA grade Ⅰ or Ⅱ were selected for endotracheal intubation general anesthesia. Dixon sequential method was adopted. The initial dose of esketamine was 0.5 mg/kg, and the dose of the next patient was determined according to the tracheal intubation response. The ratio of adjacent doses was 1:1.1. The ED₅₀ and 95% confidence interval （CI） of esketamine for inhibiting tracheal intubation response during the induction of dexmedetomidine combined with lidocaine OFA were calculated. Results A total of 29 patients were included for statistical analysis. Tracheal intubation reaction was positive in 15 cases （positive group） and negative in 14 cases （negative group）. In the positive group, 3 cases had cough reaction during tracheal intubation. The ED₅₀ of esketamine for inhibiting tracheal intubation response during the induction of dexmedetomidine combined with lidocaine OFA was 0.448 mg/kg, and the corresponding 95%CI was 0.421-0.476 mg/kg. Conclusion In the OFA of esketamine combined with dexmedetomidine and lidocaine, 0.448 mg/kg of esketamine results in 50% of the maximum response intensity for inhibiting tracheal intubation response.