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Background: Vonoprazan, a novel acid suppressant, has recently emerged as a regimen for eradicating Helicobacter pylori. However, uncertainties exist about the effectiveness and safety of VPZ‐based regimens compared with those of bismuth‐based quadruple therapy in eradicating H. pylori. The present meta‐analysis was performed to compare the effectiveness and safety of vonoprazan‐based regimens with those of bismuth quadruple therapy in eradicating H. pylori. Materials and Methods: All randomized controlled trials and non‐randomized controlled trials comparing the vonoprazan‐based therapy with the bismuth quadruple therapy were included in this meta‐analysis. Information was also extracted by two evaluators, and if heterogeneity existed, a random‐effects model was used to calculate the combined relative ratio and 95% confidence interval; otherwise, a fixed‐effects model was used. And subgroup analyses were performed to explore the sources of heterogeneity. Results: A total of 10 studies, comprising 2587 patients were included in the meta‐analysis. The results showed that the combined eradication rate of patients treated with the vonoprazan‐based regimen was significantly higher than that of patients treated with bismuth quadruple therapy, in both intention‐to‐treat and per‐protocol analyses, and the differences were statistically significant. Among the intention‐to‐treat analyses results: (90.28% vs. 83.64% [odds ratio (OR) = 1.85, 95% confidence interval (CI) (1.27, 2.70), p = 0.001]); in the per‐protocol analyses: (94.80% vs. 89.88%, [OR = 2.25, 95% CI (1.37, 3.69), p = 0.001]). The occurrence of adverse events was significantly lower in patients treated with vonoprazan‐based regimens than in those treated with bismuth quadruple therapy, (14.50% vs. 25.89%, [OR = 0.49, 95% CI (0.32, 0.75), p = 0.001]). Conclusions: For eradicating H. pylori, vonoprazan‐based regimens are remarkably advantageous over bismuth quadruple therapy. Furthermore, vonoprazan‐based regimens exhibit a lower rate of adverse events than bismuth quadruple therapy. [ABSTRACT FROM AUTHOR]