Background: This study aims to investigate the analgesic efficacy of ketamine and neostigmine as adjuvants to local anesthetic in ultrasound-guided Serratus anterior plane block for patients undergoing Modified Radical Mastectomy. Methods: Ninety female patients aged 20-65 who were scheduled for a modified radical mastectomy under-combined general anesthesia and preoperative Serratus Anterior Plane Block were included. Three local anaesthetic mixtures were used, either 30 ml bupivacaine 0.25% + 1 ml ketamine (50 mg) (Group K) or 30 ml bupivacaine 0.25% + 1 ml neostigmine (500 μg) (Group N) or 30 ml bupivacaine 0.25% + 1 ml normal saline (Group S). The first 24 hours of postoperative morphine consumption was set as the primary outcome Results: the 24 hr postoperative morphine consumption median was 3.0 (0.0-9.0) for group (S), 1.5 (0.0-4.0) for group (N) and 0.0 (0.0-4.0) mg for group (K) with statistical significant (P value 0.045). The first postoperative analgesic request was insignificant between group (K), group (N) and group (S) was (6.14 ± 5.17), (6.67 ± 3.18) and (5.89 ± 4.4 hr), respectively. The Intraoperative Fentanyl consumption showed a significant reduction in group (N) and group (K) (111.67 ± 30.64 and 110.00 ± 20.34, respectively) compared to group (S) (131.67 ± 42.51 μg). The numerical rating scale did not differ between study groups except at 8 th and 16 th hrs. Postoperatively. Conclusion:The addition of 50 mg ketamine to 0.25% bupivacaine during preoperative ultrasound-guided SAPB combined with GA in female patients undergoing modified radical mastectomy decreased the 24 hr postoperative morphine consumption and the intraoperative fentanyl requirements while adding 500 µg neostigmine decreased the intraoperative fentanyl requirements. Clinical trial registration:The study was registered at clinicaltrials.gov (NCT 04544228).