Background <p>Calcitonin gene-related peptide is an emerging therapeutic target in cluster headache, yet evidence on the preventive efficacy and safety of calcitonin gene-related peptide antagonists remains limited. This systematic review and meta-analysis assessed the efficacy and safety of calcitonin gene-related peptide antagonists in adults with Cluster headache.</p> Methods <p>We searched PubMed, Web of Science, Cochrane CENTRAL, ClinicalTrials.gov, and EBSCO for randomized controlled and single-arm trials involving episodic and chronic cluster headache. Safety outcomes evaluate the treatment-emergent adverse events, serious adverse events, and treatment discontinuations, while efficacy outcomes included the change from baseline in the mean number of weekly attacks, the proportion of participants achieving a ≥ 50% or ≥ 30% reduction in weekly attack frequency, and those reporting a “much improved” or “very much improved” status on the Patient Global Impression of Change scale.</p> Results <p>Four randomized controlled trials and two single-arm trials were included. Calcitonin gene-related peptide antagonists reduced weekly attacks by a mean of -7.23 (95% CI: − 9.86 to − 4.60). ≥ 50% responder rate was 46% (95% CI: 26%-67%) and ≥ 30% responder rate was 59% (95% CI: 45%-73%). Efficacy effects were larger in episodic than in chronic Cluster headache. The pooled proportion of patients experiencing at least one TEAE was 60% (95% CI: 35%-82%). SAEs (4%, 95% CI: 1%-9%) and discontinuations (3%, 95% CI: 1%-7%) were uncommon.</p> Conclusion <p>Calcitonin gene–related peptide antagonists provide preventive benefit with acceptable safety in cluster headache. These findings should be interpreted as supportive but less definitive. Larger, long-term, placebo-controlled randomized trials are needed to confirm efficacy and guide clinical use.</p>