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Background Whether the incorporation of Saccharomyces boulardii (S. boulardii) into vonoprazan–amoxicillin dual therapy contributes to improved eradication rate and a lower frequency of adverse events in rescue regimens for Helicobacter pylori (H. pylori) infection has yet to be established.Methods In a single-center, randomized controlled trial, 190 adults with previous H. pylori treatment failure were assigned to receive either vonoprazan (20 mg twice daily) plus amoxicillin (750 mg three times daily) (VA group) or the same regimen with S. boulardii (250 mg twice daily) (VAS group) for 14 days. Eradication rates, compliance, adverse events, and safety were assessed. Risk factors influencing the eradication rate were explored.Results Based on intention-to-treat analysis, H. pylori eradication rates were 80.0% in the VA group and 92.6% in the VAS group (P = 0.011), and per-protocol analysis yielded eradication rates of 85.4% and 94.6%, respectively (P = 0.037). There were no significant differences in eradication rates for either the VA regimen (P = 0.736) or the VAS regimen (P = 0.431) based on the number of previous treatment failures. However, a history of prior furazolidone use reduced the eradication rate of VAS therapy. The incidence of adverse events was significantly lower in the VAS group (11.6%) than in the VA group (32.6%; P<0.001). Both groups showed similar good compliance and safety.Conclusions Supplementing vonoprazan–amoxicillin dual therapy with S. boulardii significantly increases H. pylori eradication rates and reduces adverse events, offering an effective and simple rescue treatment unaffected by previous treatment failures.