Abstract Study objective Patients undergoing open nephrectomy surgery experience severe perioperative pain, which is primarily due to incision of several muscles. Abdominal wall blocks are known to reduce pain without causing epidural-associated hypotension. We conducted this study to compare unilateral ultrasound-guided transmuscular quadratus lumborum block and posterior transversus abdominis block in combination with general anesthesia alone in terms of intraoperative and postoperative analgesics and hemodynamics and postoperative complications. Methods This was a randomized, double-blinded, controlled trial conducted in the operating room. This study included 48 patients aged 20-60 years, with ASA I and II, and a body mass index ≤ 30 kg.m-2 who were scheduled for open nephrectomy procedure.The 48 patients scheduled for nephrectomy were randomly allocated into one of the following three groups after induction of general anesthesia: Group A (n = 16) received USG transmuscular QLB; Group B (n = 16) received unilateral USG posterior transversus abdominis plane (TAP) block; and Group C (n = 16; control group) did not receive any blocks. Introperative fentanyl consumption, and hemodynamics (heart rate and mean arterial pressure (MAP)) were recorded after anesthesia induction, at surgical incision, and every 15 min till the end of surgery. Visual Analogue Scale (VAS) was evaluated immediately at 30 min and 1,2,4,6, and 12 hours postoperatively. The time of first analgesic request was also recorded. Results Intraoperative fentanyl consumption (µg) was significantly lower in Groups A and B (164.69 ± 27.35 and 190.31 ± 44.48, respectively) than in Group C (347.50 ± 63.64) (p < 0.001). Postoperatively, total pethidine consumption was significantly lower in Groups A and B than in Group C (85.31 ± 6.68, 84.06 ± 4.17 mg, and 152.19 ± 43.43 mg, respectively) (p < 0.001. Time to rescue analgesia was longer in Groups A and B than in Group C (138.75 ± 52.39 min, 202.50 ± 72.25 min, and 37.50 ± 13.42 min, respectively) (p < 0.001). VAS score was significantly lower in Groups A and B than in Group C at 30 min and 1, 2, 4, and 6 hours postoperatively. Conclusion Transmuscular quadratus lumborum block and posterior transversus abdominis blocks were effective in providing perioperative analgesia in patients undergoing open nephrectomy. However, quadratus lumborum block provided superior analgesia.