Background: Biologics have transformed the management of severe asthma, offering targeted mechanisms to modulate inflammatory pathways. Despite the growing number of approved agents—targeting IgE, IL-5, IL-4/13, and other mediators—uncertainty persists regarding their relative efficacy and safety profiles. This systematic review and meta-analysis compares the clinical outcomes of key biologic therapies in patients with severe, uncontrolled asthma. Methods: We searched PubMed, Embase, and Cochrane central from January 2016 to March 2023 for randomized managed trials (RCTs) investigating omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, or tezepelumab in severe asthmatic populations. two reviewers independently screened titles/abstracts, assessed complete texts for eligibility, and extracted final results facts on exacerbation rates, lung function, oral corticosteroid use, and adverse events. threat of bias was appraised using the Cochrane hazard of Bias 2 tool. wherein viable, a random-effects meta-evaluation turned into done to compute pooled effect sizes for annualized exacerbation charges, alternate in compelled expiratory quantity in one 2nd (FEV₁), and discontinuation rates because of destructive occasions. Results: Nineteen RCTs (n=8,762 participants) met inclusion criteria. All studies reported improvements in exacerbation frequency and FEV₁ with active biologic treatment compared to placebo. In meta-analysis, omalizumab and anti–IL-5 agents (mepolizumab, reslizumab, benralizumab) yielded similar reductions in annualized exacerbations (rate ratio range: 0.49–0.57). Dupilumab consistently demonstrated robust lung function gains (mean FEV₁ improvement: +0.31 L [95% CI, 0.25–0.37]), whereas tezepelumab appeared promising for broader phenotypes. Overall adverse event profiles were comparable among agents, although injection site reactions were slightly more common with dupilumab. Discontinuations due to adverse events did not differ significantly across interventions (p=0.62, I²=34%). Discussion: The present synthesis indicates that biologic therapies substantially curtail exacerbations and enhance lung function in severe asthmatics, with generally favorable safety profiles. Although anti–IL-5 therapies excel in eosinophilic phenotypes and dupilumab confers robust FEV₁ gains, no single agent definitively outperforms the rest in all outcomes. Personalized selection based on biomarkers (e.g., eosinophil counts, IgE levels, Type 2 inflammation markers), comorbidities, and patient preferences remains crucial. Further head-to-head trials with standardized endpoints will refine these comparative insights and optimize therapy choice for severe asthma.