Objective To explore the effects of quadratus lumborum block combined with oxycodone on the perioperative stress response， serum substance P （SP）， and prostaglandin E2 （PGE2） in patients undergoing laparoscopic transabdominal radical resection of rectal cancer. Methods A prospective， non-randomized controlled design was employed. From January 2023 to June 2025， a total of 150 patients who underwent laparoscopic transabdominal radical resection of rectal cancer in the hospital were recruited. Group allocation was determined based on the anesthesiologist's decision and the patient's preference. There were 77 cases in the control group ［quadratus lumborum block （20 mL of 0.375% ropivacaine） after tracheal intubation + fentanyl analgesia during the perioperative period］ and 73 cases in the study group ［quadratus lumborum block combined with oxycodone anesthesia （intravenous injection of 0.1 mg/kg oxycodone during anesthesia induction and 0.05 mg/kg oxycodone 30 min before the end of surgery）］. The changes in mean arterial pressure （MAP） and heart rate （HR） at different time points ［before surgery （T0）， before intubation （T1）， immediately after pneumoperitoneum （T2）， immediately after intestinal anastomosis （T3）， at the end of surgery （T4）］ were compared between the two groups. The perioperative indexes （operation time， intraoperative blood loss， first time out of bed， exhaust time， frequency of analgesic pump presses within 48 h after surgery） were recorded. The levels of stress indexes ［cortisol （Cor）， norepinephrine （NE）， C-reactive protein （CRP）， tumor necrosis factor-α （TNF-α）］， serum SP and PGE2 were compared before surgery and 1 day after surgery， and adverse reactions were recorded. Results Compared with T0， both mean arterial pressure （MAP） and heart rate （HR） increased at T1 and T2 in both groups. The increasing trend of MAP and HR in the study group was lower than that in the control group （P < 0.05）. At T3， the HR in the study group was lower than that in the control group （P < 0.05）. There was no significant difference in the operation time or intraoperative blood loss between the two groups （P > 0.05）. However， the postoperative first leaving-bed time， exhaust time， and the frequency of analgesic pump presses within 48 hours after surgery in the study group were shorter or lower than those in the control group （P < 0.05）. One day after surgery， the levels of cortisol （Cor）， norepinephrine （NE）， C-reactive protein （CRP）， tumor necrosis factor-α （TNF-α）， substance P （SP）， and prostaglandin E2 （PGE2） increased in both groups， but these levels were lower in the study group than in the control group （P < 0.05）. There was no significant difference in the incidence of postoperative adverse reactions between the two groups （P > 0.05）. Conclusion Quadratus lumbarum block combined with oxycodone can stabilize the peri-operative stress response， mitigate the increasing trend of serum SP and PGE2 levels in patients undergoing laparoscopic transabdominal radical resection of rectal cancer， which is beneficial for the early postoperative recovery of patients with rectal cancer.