Background <p>Monoclonal antibody therapies targeting specific inflammatory pathways have shown potential in treating chronic obstructive pulmonary disease (COPD). However, the efficacy and safety of these treatments across different patient phenotypes remain uncertain.</p> Methods <p>This meta-analysis included 15 registered randomized controlled trials (RCTs) evaluating monoclonal antibodies targeting type 2 and non-type 2 inflammatory pathways in COPD. The primary outcomes assessed were rates of moderate to severe exacerbations, rates of severe exacerbations, lung function (pre- and post-bronchodilator FEV₁), St. George’s Respiratory Questionnaire (SGRQ) scores, and safety-related events. Subgroup analyses were performed based on inflammatory phenotype, exacerbation frequency, and smoking status. Meta-regression was used to examine the influence of covariates, such as baseline FEV₁%pred and other demographic factors.</p> Results <p>Monoclonal antibody therapies significantly reduced the rates of moderate to severe exacerbations (RR 0.88, 95% CI 0.83–0.93) and severe exacerbations (RR 0.82, 95% CI 0.72–0.94). Subgroup analyses revealed more pronounced benefits in eosinophilic and frequent exacerbator phenotypes. Non-eosinophilic patients demonstrated a better response to IL-33-targeting therapies. Lung function and quality of life showed modest improvements across most therapies. Smoking status and baseline FEV₁ were significant modifiers of treatment efficacy. No significant increase in serious adverse events was noted.</p> Conclusions <p>Monoclonal antibody therapies, particularly those targeting type 2 inflammation, effectively reduce exacerbation rates in COPD, with greater benefits observed in patients with eosinophilic phenotypes and frequent exacerbations. Baseline lung function also influences treatment response. These findings underscore the importance of personalized, phenotype-driven treatment approaches and support the continued development of biologics for COPD management.</p>