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Gastroesophageal reflux disease (GERD) is a chronic relapsing disorder often inadequately controlled with proton pump inhibitors (PPIs), particularly in patients with nocturnal acid breakthrough (NAB) or non‐erosive reflux disease (NERD). Tegoprazan, a potassium‐competitive acid blocker (PCAB), offers rapid, potent, and CYP2C19‐independent acid suppression. This systematic review and meta‐analysis evaluated randomized controlled trials comparing Tegoprazan with PPIs in adults with GERD and related disorders. Databases searched included PubMed, Cochrane, Wiley, and ClinicalTrials.gov (2015–2026). Eighteen studies met inclusion criteria. In erosive esophagitis, Tegoprazan 50 mg once daily achieved mucosal healing rates of 91.1%–99.1%, non‐inferior to PPIs (93.5%–98.9%; pooled RR = 1.01, 95% CI 0.98–1.05). Pharmacodynamic and clinical studies demonstrated faster acid suppression and improved nocturnal pH control versus PPIs, achieving pH ≥ 4 within 30–60 min and maintaining levels throughout the 12‐h period. In nocturnal symptom analyses, Tegoprazan achieved earlier relief (1.5 vs. 3 days to first heartburn‐free night) and higher proportions of heartburn‐free nights (57.8% vs. 43.1%), with significantly greater complete (p = 0.038) and partial (p = 0.034) nighttime symptom resolution than Esomeprazole. In NERD, symptom resolution ranged from 42.5% to 48.9% versus 24.2% with placebo. In open‐label functional dyspepsia cohorts, improvements ranged from 74.6% to 86.7% in open‐label cohorts. Seven trials (n = 2492) showed higher Helicobacter pylori eradication with Tegoprazan‐based therapy (RR = 1.05, 95% CI 1.01–1.09; p = 0.006; I2 = 0%). Adverse events were mild and comparable to PPIs. Tegoprazan provides rapid, sustained acid suppression, effective nocturnal symptom control, and a modest but statistically significant improvement in H. pylori eradication, representing a potential alternative to PPIs for patients with persistent or CYP2C19‐related variable response.