Objective: To compare the clinical efficacy of a simplified opioid-free general anesthesia (OFGA) regimen based on dexmedetomidine and lidocaine combined with quadratus lumborum block (QLB) versus traditional opioid-based general anesthesia with QLB in patients undergoing laparoscopic radical prostatectomy (LRP). Methods: A retrospective cohort study included 120 patients, divided into two groups: the simplified OFGA group (n = 56) and the traditional opioid-based anesthesia group (n = 64). All patients received ultrasound-guided bilateral QLB. The primary outcomes were total opioid consumption within 48 hours postoperatively (converted to morphine milligram equivalents, MME) and intraoperative opioid rescue rate. Secondary indicators include the postoperative Numerical Rating Scale (NRS) score at rest, recovery quality indicators, and adverse events. Results: The simplified OFGA group exhibited significantly lower total opioid consumption within 48 hours postoperatively but required higher intraoperative opioid rescue rates compared to the traditional opioid-based group (P<0.001). Generalized estimating equations (GEE) analysis revealed a significant interaction between group and time for NRS pain scores (P<0.05), with post-hoc comparisons showing higher scores in the OFGA group at 12, 24, and 48 hours postoperatively (P<0.05). The OFGA group demonstrated higher effective pressing frequency ratio of the patient-controlled analgesia pump, shorter emergence time, earlier first ambulation, and faster first flatus (P<0.001). Regarding safety, the OFGA group had a lower incidence of postoperative nausea and vomiting (PONV; P<0.05) but experienced more frequent intraoperative hypotension and bradycardia (P<0.05). Conclusion: In LRP patients receiving QLB, the simplified OFGA regimen combining dexmedetomidine and lidocaine effectively reduces postoperative opioid consumption and PONV while accelerating early recovery. However, it may compromise mid-to-late postoperative analgesia and increase intraoperative hemodynamic fluctuations. This approach represents a viable opioid-sparing strategy.