Background: Major abdominal surgeries encompass all gastrointestinal (colorectal, gastric, small bowel, hepatic, pancreatic resections), urological (nephrectomy, cystectomy, prostatectomy), and gynecological (uterine and ovarian resections, pelvic floor reconstructions) procedures performed for any indication, their duration is more than 1 hr. Pain control in major abdominal surgeries is a big deal for patient satisfaction, especially for anesthetic benefits. Objective: To compare the effects of intravenously administered opioids and non-opioids on pain relief in major abdominal surgeries. Patients and Methods: This study is a prospective comparative randomized trial. Two equal groups; opioid free anesthesia (OFA) group and opioid based anesthesia (OBA) group, of thirty patients each were randomly selected from a total of sixty adult patients of both sexes, ASA I, II, and III ranging in age from 30 to 70, scheduled for elective major abdominal surgeries under general anesthesia between August 2023 and April 2024 at Menoufia University hospitals. Results: OFA group had lower VAS scores than OBA group at 30, 60, 90 min. postoperatively (p <0.05). While there were higher statistically significant, but clinically insignificant changes in MAP and heart rate (HR) in OBA group (p < 0.05 for both). The mean Drug dose (mg) and 1^st call for rescue analgesia (Hr.) were lower in the OBA group (p < 0.05). Both groups had no statistically difference regarding postoperative complications. Conclusion: OFA, compared to OBA, is associated with lower postoperative VAS scores and less analgesic consumption when used to control postoperative pain in major abdominal surgeries.