Migraine is a prevalent and disabling neurological disorder characterized by episodic or chronic headaches, often associated with nausea, vomiting, and sensory hypersensitivity. Traditional pharmacotherapy includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, beta-blockers, anticonvulsants, and antidepressants, but these approaches often exhibit variable efficacy, poor tolerability, and contraindications in certain populations. Recent advancements in migraine treatment have introduced calcitonin gene-related peptide (CGRP) inhibitors, a novel class of targeted therapies that modulate the neurovascular mechanisms underlying migraine pathophysiology. However, comparative clinical efficacy and real-world outcomes between traditional pharmacotherapy and CGRP inhibitors remain inadequately explored. A randomized controlled trial (RCT) was conducted with 300 migraine patients (150 in the CGRP inhibitor group, 150 in the traditional therapy group) over 24 weeks. Participants were randomized using Epi Info™ software for sample size determination and stratified based on migraine frequency and severity. Inclusion criteria involved adults (18–65 years) with a diagnosis of episodic or chronic migraine, while those with secondary headaches, pregnancy, or contraindications to study drugs were excluded. The primary endpoints included the reduction in monthly migraine days (MMDs), responder rates (≥50% reduction in MMDs), and mean pain severity scores. Secondary outcomes assessed adverse events and patient-reported disability. Results demonstrated that the CGRP inhibitor group achieved a significant reduction in MMDs (−7.2 ± 1.5 days) compared to traditional therapy (−4.1 ± 1.8 days, p < 0.001). The responder rate was higher in CGRP users (68.5%) versus traditional therapy (42.7%, p < 0.001). Pain intensity scores decreased significantly in both groups, but the CGRP group exhibited superior tolerability with fewer discontinuations due to adverse events (7.2% vs. 16.5%, p = 0.004). This study provides strong evidence supporting the clinical superiority of CGRP inhibitors over traditional pharmacotherapy in terms of efficacy, adherence, and safety. These findings highlight the need for individualized treatment strategies and advocate for CGRP inhibitors as first-line options in select patient populations. Future research should explore long-term safety, cost-effectiveness, and real-world treatment outcomes to optimize migraine management.