Objective To observe the efficacy and safety of esketamine combined with propofol anesthesia in painless bronchoscopy. Methods The prospective study enrolled 90 patients with painless bronchoscopy from September 2020 to November 2021 and divided them into two groups according to the ratio of 1：1. The patients in the observation group （45 cases） were given esketamine combined with propofol anesthesia, and the patients in the control group （45 cases） were given sufentanil combined with propofol. The two groups were compared in terms of MAP, HR, and anesthesia safety before anesthesia （T0）, before painless bronchoscopy （T1）, when bronchoscope passes through glottis （T2）, when bronchoscope reaches carina （T3）, when fiberoptic bronchoscope is taken out （T4）, when the patient wakes up （T5）, and 30 min after examination （T6）. Results The fluctuation ranges of MAP at T1, T2, and T3 in the observation group were lower than those in the control group （P<0.05）. The fluctuation ranges of HR in the observation group at T2, T3, T4, and T6 were lower than those in the control group （P<0.05）. The SpO₂ values at T3 and T4 in the observation group were higher than those in the control group （P<0.05）. The incidence rate of cough, anesthesia awakening time, and anesthesia awareness time in the observation group were lower than those in the control group （P<0.05）. The incidence rate of adverse reactions was 6.67% （3/45） in the observation group and 26.67% （12/45） in the control group （P<0.05）. Conclusion Compared with sufentanil, the anesthesia scheme of esketamine combined with propofol can make hemodynamics more stable and reduce complications obviously.