BACKGROUND: Limited data from randomized controlled trials (RCTs) indicate that lorundrostat, an aldosterone synthase inhibitor, may be effective in managing uncontrolled hypertension (HTN). Currently, no systematic review or meta-analysis (SR/MA) has assessed the safety and efficacy of the drug in such clinical conditions; this SR/MA aims to fill that knowledge gap. METHODS: Electronic databases and registers were searched from inception to June 30, 2025, for RCTs involving lorundrostat in the intervention arm and placebo in the control arm in individuals with uncontrolled HTN. The primary outcome was lorundrostat safety; additional outcome was its efficacy in lowering blood pressure (BP). Meta-analyses were conducted using the RevMan web with random-effects models, presenting results as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: Three low-bias RCTs with 1568 subjects were included. Over 6-12 weeks, lorundrostat (50 mg: RR 1.4 [1.23, 1.63]; 100 mg: RR 1.49 [1.29, 1.72]) increased risks of any adverse events (AEs), but not serious AEs, compared to placebo. Lorundrostat at both doses increased the risk of symptomatic hypotension. The lorundrostat group experienced a larger decrease in estimated glomerular filtration rate and an increase in serum potassium levels. Lorundrostat 50 mg lowered office systolic (MD -11.11 mm Hg) and diastolic BP (MD -3.87 mm Hg) more than placebo, but not 24-hour ambulatory systolic BP. Lorundrostat 100 mg lowered office systolic (MD -8.09 mm Hg) and 24-hour ambulatory systolic BP (MD -7.18 mm Hg) more than placebo, but did not affect office diastolic BP. CONCLUSION: Lorundrostat effectively manages uncontrolled HTN but increases the risk of some AEs. More RCTs involving diverse populations are needed to improve clinical decision-making.