A meta-analysis compared vonoprazan-amoxicillin dual therapy (VPZ-HDDT) with proton pump inhibitor-based dual therapy (PPI-HDDT) as first-line treatment for Helicobacter pylori eradication. It included four randomized controlled trials with 1,807 patients. In an intention-to-treat (ITT) analysis, VPZ-HDDT achieved an eradication rate of 88.0% versus 82.7% for PPI-HDDT (RR = 1.04, 95% CI: not specified, P = 0.04, I² = 28%). In the per-protocol (PP) analysis, the eradication rate was 92.3% for VPZ-HDDT versus 87.3% for PPI-HDDT (RR = 1.04, 95% CI: 1.01–1.08, P = 0.02). Adverse events occurred in 8.6% of patients in the VPZ-HDDT group versus 10.6% in the PPI-HDDT group (RR = 0.78, 95% CI: 0.59–1.04, P = 0.09), with no statistically significant difference. Compliance with treatment was 97.1% for VPZ-HDDT versus 95.6% for PPI-HDDT (RR = 1.02, 95% CI: 0.99–1.05). VPZ-HDDT shows a higher eradication rate with comparable safety and compliance.