Objective To evaluate the safety and effectiveness of esketamine combined with propofol in painless bronchoscopy anesthesia. Methods A total of 62 patients who underwent painless bronchoscopy in Beijing Chest Hospital Affiliated to Capital Medical University from January to March 2021 were enrolled. According to the random number table method, they were divided into two groups: a control group (n=30) and an observation group (n=32). The control group was anesthetized with propofol combined with sufentanil, while the observation group was anesthetized with esketamine combined with propofol. Then, their systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, pulse oxygen saturation (SpO2) and recovery time, Steward recovery score and the incidence of adverse reactions were recorded before anesthesia (T0), after anesthesia (T1), when the bronchoscope was inserted into the glottis (T2), and during the examination (T3). Results There was no significant difference between the two groups in SBP, DBP, heart rate, and SpO2 at T0 (P>0.05). The observation group presented increases in SpO2 at T1, T2, and T3 compared with the control group (P<0.05). The observation group showed increases in SBP, DBP, heart rate at T1 and T3, as well as decreases in SBP, DBP, and heart rate at T2, compared with the control group (P<0.05). The recovery time was shorter in the observation group than that of the control group (P<0.05). There was no significant difference between the two groups in Steward recovery score and the incidence of adverse reactions (nausea and vomiting) (P>0.05). Conclusions The use of esketamine combined with propofol in painless bronchoscopy anesthesia has smooth circulation and breathing, rapid postoperative recovery, and good controllability, with high clinical application value.