Abstract Background Postoperative pain control in neurosurgical patients particularly after elective craniotomy remains clinically challenging due to the need for early neurological assessment and the adverse effects associated with opioid use. This study aimed to compare the efficacy and safety of an opioid-sparing multimodal analgesia (MMA) protocol versus a conventional opioid-based regimen for managing post-craniotomy pain. Methodology This prospective, randomized controlled trial was conducted over 12 months at Zagazig University Hospitals and included 60 adult patients (aged 18–65 years, American Society of Anesthesiologists )ASA( physical status I–II) scheduled for elective supratentorial craniotomy with planned postoperative intensive care unit (ICU) admission. Patients were randomly assigned in a 1:1 ratio to either a multimodal opioid-sparing analgesia group (Group M, n=30) or a conventional opioid-based analgesia group (Group O, n=30) using simple randomization. The MMA protocol included preoperative oral gabapentin, intraoperative dexmedetomidine infusion, a postoperative scalp block with bupivacaine, and scheduled intravenous (IV) acetaminophen and ketorolac. The opioid group received scheduled IV morphine according to institutional practice. The primary outcome was the Visual Analog Scale (VAS) score at 2 h postoperatively. Secondary outcomes included time to first rescue analgesia, total opioid consumption, sedation scores, oxygen saturation, postoperative nausea and vomiting (PONV), and patient satisfaction. Results VAS scores were significantly lower in Group M at 1, 2, and 4 h postoperatively (P=0.046, 0.039, and 0.045, respectively). A highly significant difference in sedation scores was observed between the groups at 30 min, 1 h, and 4 h (P<0.001). Additionally, Group M had a significantly lower frequency of vomiting (P=0.034); however, excellent satisfaction scores were more frequently reported in Group O, despite the objectively superior analgesic and safety profile observed in Group M. Conclusion In this randomized controlled trial, opioid-sparing MMA provided superior postoperative pain control after elective craniotomy, with fewer adverse effects compared to conventional opioid-based regimens. These results