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Purpose The aim of study was to explore the overall efficacy and safety of ultrasound-guided quadratus lumborum block combined with general anesthesia in patients undergoing percutaneous nephrolithotomy (PCNL). Methods The study included 76 patients who underwent PCNL at our hospital between October 2018 and October 2019. The patients were randomly divided into the study group (ultrasound-guided quadratus lumborum block combined with general anesthesia, 38 cases) and the control group (general anesthesia, 38 cases). The intraoperative estimated blood loss, operative time and intraoperative anesthetic usage were recorded. Moreover, the effective pressing times of the posterior cerebral artery (PCA), the dosage of sufentanil in patient controlled intravenous analgesia (PCIA) were observed within 48 hours after operation. Results The dosage of propofol and remifentanil, the time of intestinal exhaust recovery time and the hospital study in the study group were lower than those in the control group. The HR and MAP of the two groups, with a trend towards gradual decrease at T0 and T1, were lower than those at T0. At 2 h, 6 h, 8 h and 24 h after operation, the visual analogue scale/score (VAS) score of the study group was lower than that of the control group. The analgesic rescue rate, the dosage of sufentanil and the effective PCA compression times in the study group were lower than those in the control group. The total incidence of adverse reactions in postanesthesia care unit (PACU) in the study group was significantly lower than that in the control group (8/38 vs. 18/38). Conclusion The combination of ultrasound-guided quadratus lumborum block and general anesthesia effectively exerts beneficial outcomes in terms of validly reducing the dose of tranquilizers and anesthetic analgesics during PCNL, which is able to treat patients with anesthetic mode of low opioids.