Background: Hypertension is a majore global cardiovascular risk factor in spite of various available antihypertensive drug classes. Poor adherence and suboptimal blood pressure (BP) control prove the need for novel, durable therapeutic options. Zilebesiran, a subcutaneously administered RNA interference (RNAi) therapeutic targeting hepatic angiotensinogen synthesis, provides long-acting BP reduction through twice-yearly dosing. Objectives: To systematically evaluate the efficacy and safety of zilebesiran in adult patients with hypertension, synthesising data from early-phase clinical trials. Methods: A systematic review and meta-analysis were conducted including data from four trials—Desai et al. (Phase 1), KARDIA-1, KARDIA-2, and KARDIA-3 (Phase 2). Eligible studies enrolled adults (≥18 years) with primary hypertension treated with zilebesiran as monotherapy or add-on therapy. Primary efficacy outcomes were change in systolic and diastolic BP (office and ambulatory). Safety outcomes are adverse events (AEs), serious AEs (SAEs), and mortality. Pooled analyses were done using random-effects (DerSimonian–Laird) models, with heterogeneity assessed by I² statistics. Results: Among 821 zilebesiran-treated participants, pooled mean reduction in ambulatory systolic blood pressure(SBP) was −6.81 mm Hg and in office SBP −6.60 mm Hg. Ambulatory and office DBP reductions averaged −5.8 mm Hg and −6.6 mm Hg. Overall AE rate was 23.7%, SAEs 4.6%, and mortality 0.4%. Common AEs were injection-site reactions (≈10%) and mild headache or dizziness; hepatic, renal, or cardiac events were infrequent. Conclusion: Zilebesiran showed consistent, clinically meaningful BP reductions and an acceptable short-term safety profile across Phase 1–2 studies. Its 6 montly dosing provides promising strategy to improve adherence in hypertension management. Larger, long-term outcome trials are needed to confirm durability, cardiovascular benefits, and cost-effectiveness.