Objective To study the feasibility of not using opioids in ureteroscopic holmium laser lithotripsy under general anesthesia with laryngeal mask airway. Methods Patients with elective lithotripsy who were diagnosed and treated in Xuzhou City Hospital of Traditional Chinese Medicine between August 2022 and February 2023 were enrolled as study subjects and randomly divided into an experimental group of 30 cases and a control group of 30 cases. Both groups were given 0.4 μg/（kg·h） dexmedetomidine pump 10 min before anesthesia induction. The experimental group was given 0.3 mg/kg esketamine, and the control group was given fentanyl during anesthesia induction. The experimental group was given 0.1 mg/kg ketamine combined with propofol pump, and the control group was given remifentanil combined with propofol pump during anesthesia maintenance. The mean arterial pressure （MAP） and heart rate （HR） were compared between the two groups at 10 min before anesthesia induction （T0）, at the time of loss of consciousness （T1）, immediately after insertion of laryngeal mask airway （T2）, at the beginning of the surgery （T3）, at the end of the surgery （T4）, and at the time of extraction of laryngeal mask airway （T5）. The dosage of propofol and the use of intraoperative vasoactive drugs were recorded. The recovery time of spontaneous breathing, laryngeal mask airway removal time, postoperative nausea and vomiting, postoperative 30 min visual analogue scale （VAS） score, and the number of cases who required additional nonsteroidal anti-inflammatory drugs （NSAIDs） at postoperative 4 h were also compared between the two groups. Results At T1, the MAP and HR in the experimental group were higher than those in the control group （P<0.05）, and there was no significant difference at other time points （P>0.05）. The dosage of propofol in the experimental group was significantly less than that in the control group during anethesia maintenance （P<0.05）. The cases who used intraoperative vasoactive drugs in the experimental group was less than the cases in the control group, but no statistical difference was found （P>0.05）. There was no statistical difference in the recovery time of spontaneous breathing and laryngeal mask airway removal time between the two groups （P>0.05）. Three patients in the experimental group experienced postoperative nausea and vomiting, and the number was 5 in the control group, with no difference （P>0.05）. The resting VAS score at 30 min after surgery in the experimental group was significantly lower than that in the control group （P<0.05）. Three patients in the experimental group took oral analgesic after surgery, and 5 patients in the control group did, with no difference （P>0.05）. Conclusion Esmketamine combined with dexmedetomidine and NSAIDs makes it possible not to use opioids during ureteroscopic holmium laser lithotripsy under general anesthesia with laryngeal mask airway.