BACKGROUND: Aldosterone synthase inhibitors (ASIs) have emerged as a mechanistically targeted strategy for resistant and uncontrolled hypertension; however, no head-to-head trials exist, and comparative efficacy and safety remain uncertain. We compared their efficacy and safety using network and pairwise meta-analysis of randomized trials. METHODS: This systematic review and meta-analysis adhered to the PRISMA guidelines. PubMed/MEDLINE, Scopus, Embase, ClinicalTrials.gov, and Cochrane Library were searched from inception to January 14, 2026, for randomized trials evaluating ASIs versus placebo or standard care. A frequentist random-effects network meta-analysis assessed systolic (SBP) and diastolic blood pressure (DBP). Dichotomous safety outcomes were pooled using Hartung-Knapp random-effects models. Network consistency was evaluated using design-by-treatment interaction modeling. Prespecified subgroup analyses stratified outcomes by hypertension phenotype (resistant vs uncontrolled). RESULTS: Across 7 RCTs (n = 2,828), all ASIs significantly reduced SBP versus placebo: baxdrostat -8.63 mmHg (95% CI -10.84 to -6.42), lorundrostat -7.47 mmHg (95% CI -9.54 to -5.40), and LCI699/osilodrostat -5.63 mmHg (95% CI -9.15 to -2.12), with no significant indirect differences between agents. In resistant hypertension, lorundrostat (-9.00 mmHg; 95% CI -13.19 to -4.81) and baxdrostat (-8.77 mmHg; 95% CI -10.50 to -7.05) demonstrated pronounced reductions. In uncontrolled hypertension, LCI699/osilodrostat showed the largest point estimate (-10.55 mmHg; 95% CI -16.49 to -4.61), though this derives from a single early-phase trial and requires cautious interpretation. DBP reductions were significant for baxdrostat (-3.23 mmHg; 95% CI -4.73 to -1.73) and lorundrostat (-3.60 mmHg; 95% CI -5.43 to -1.77). Hypotension (RR 2.67), hyperkalemia (RR 7.94), and hyponatremia (RR 2.07) were significantly increased; serious adverse events, discontinuation, and network inconsistency were not detected. CONCLUSIONS: ASIs provide clinically meaningful BP reduction across both hypertension phenotypes; however, short-term use is associated with hypotension and electrolyte disturbances, necessitating careful monitoring. Phenotype-specific efficacy and long-term safety require validation in outcome-driven trials. Systematic Review Registration: PROSPERO CRD420251266257.