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Background: According to the Maastricht VI/Florence consensus report, potassium‐competitive acid blockers (P‐CAB) may improve Helicobacter pylori eradication treatment. Materials and methods: A total of 213 H. pylori treatment‐naive patients aged between 18 and 70 years were treated with two regimens. The two regimens are VDT: 20 mg vonoprazan twice a day and 1 g amoxicillin three times daily and EDT: 20 mg esomeprazole four times a day and 750 mg amoxicillin four times daily. 13C‐urea breath tests were used to evaluate eradication rate 4–6 weeks after treatment. Based on propensity score matching (PSM), this retrospective study analyzed the eradication rates, adverse events (AEs), compliance, and antibiotic resistance rates in VDT and EDT groups. Results: On intention‐to‐treat (ITT) analysis, the eradication rate in VDT group (89.0%; 95% CI 81.7–96.3) was non‐inferior to that in EDT group (87.7%; 95% CI 80.1–95.3; p = 0.796). The corresponding per‐protocol (PP) eradication rates were 94.1% (95% CI 88.4–99.8) and 92.8% (95% CI 86.7–98.9; p = 1.000), respectively. There were no significant between‐group differences with respect to compliance or incidence of AEs. Conclusions: The efficacy and safety of 14‐day VDT and EDT were comparable. Therefore, 14‐day VDT or EDT may be recommended for the first‐line treatment of H. pylori infection. [ABSTRACT FROM AUTHOR]