Hypertension remains a leading modifiable risk factor for cardiovascular morbidity and mortality worldwide, yet rates of blood pressure control remain suboptimal despite the availability of multiple classes of antihypertensive agents. Zilebesiran is a novel small interfering RNA therapeutic that targets hepatic angiotensinogen messenger RNA, offering a unique upstream approach to renin-angiotensin-aldosterone system suppression. Conjugated with N-acetylgalactosamine for liver-specific delivery, zilebesiran enables sustained angiotensinogen silencing and long-lasting blood pressure reductions after a single subcutaneous injection. Preclinical studies have demonstrated potent antihypertensive effects with minimal toxicity. Phase 1 and 2 clinical trials (KARDIA-1 and KARDIA-2) confirmed its dose-dependent and durable efficacy, with significant 24-hour ambulatory systolic blood pressure reductions maintained for over 6 months. Zilebesiran also showed a favorable safety profile, with minimal adverse effects and no evidence of renal, hepatic, or electrolyte disturbances. Its long-acting mechanism, reduced dosing frequency, and potential to improve adherence make it a promising therapeutic candidate for both general and resistant hypertension. Ongoing phase 2b studies (KARDIA-3) will further clarify its utility in high-risk patients and those with chronic kidney disease.