Background: The postoperative analgesic effect of transmuscular quadratus lumborum block (QLB-TM) in patients following lower abdominal surgeries has been identified; however, the efficacy of QLB using the lateral approach (QLB-L) is still in debate. Therefore, this retrospective study was conducted to investigate the effect of a single-shot block with QLB-L on postoperative analgesia for patients undergoing percutaneous nephrolithotomy (PCNL). Methods: The medical information of the patients undergoing PCNL was retrieved from the electronic charter system (Medisystem, Suzhou, China) in our Nanjing Drum Tower Hospital during the period of Jan/2019 to Jun/2019. Among the total of 57 patients, there are 17, 18, and 22 patients subjected to QLB-L, QLB-TM, or routine treatment, respectively. The primary observational parameter was to assess postoperative pain with visual analog scales (VAS) at rest 30 min after extubation, 24 h, and 48 h after surgery, respectively. The secondary observatory endpoints, including the consumption of intraoperative opioids, the cumulative dose of non-steroid anti-inflammatory drugs (NSAIDs) and the incidence of adverse events related to postoperative analgesia, were evaluated as well. Results: The static VAS score at 24 h after surgery and the intraoperative consumption of sufentanil were significantly lower in patients receiving either intervention of QLB-L or QLB-TM as compared with those receiving routine treatment. However, one shot of QLB had no impact on VAS scores at 30 min post-extubation, 48 h after PCNL procedure compared with the patients receiving routine treatment. The percentage of non-ambulatory patients within 24 h post-PCNL was significantly higher in the QLB-TM group compared with the routine treatment group (P = 0.04). There were no significant differences in the incidence of postoperative nausea and vomit (PONV), itches, respiratory depression, the time for the first defecation, and the length of hospital stay (LOS) among the three groups. Conclusions: QLB-L procedure may exert as equivalent as QLB-TM in terms of abrogating postoperative pain within 24 h post-surgery and decreasing intraoperative sufentanil consumption in patients undergoing PCNL procedure as well. The caution should be taken to avoid lower extremities weakness in the patients after QLB-TM within the first 24 h post-PCNL procedure.