IntroductionHybrid therapy (HT) is a non-bismuth quadruple therapy created to surpassHelicobacter pylori’s (H. pylori) resistance rates to antibiotics. HT has excellent eradication rates, as well as a very good compliance and safety profile. We aim to compare HT with sequential therapy (ST) and concomitant therapy (CT) for the eradication ofH. pylori.MethodsThis systematic review was conducted following the principles of the PRISMA guidelines. Literature was electronically searched on the CENTRAL library, PubMed, Embase, Scopus, LILACS, and ClinicalTrials.gov. Only randomized controlled trials were included. The primary outcome evaluated was eradication rate ofH. pylori. The secondary outcomes evaluated were adverse events and compliance rates. Meta-analyses were performed with Cochrane Review Manager 5.4. The Mantel–Haenszel method was used to estimate the pooled relative risk and 95% confidence interval of the eradication rates between HT and other regimens, as well as the secondary outcomes.Results10 studies were included, comprising 2993 patients. The mean eradication rates achieved by HT with intention-to-treat (ITT) and per-protocol (PP) analyses were, respectively, 86% (range: 79.2–90.8%) and 91.7% (range: 82.6–96.1%). No statistically significant difference was found in ITT eradication rate between HT and CT (relative risk: 1; 95% CI: 0.96- 1.03) and between HT and ST (relative risk: 1.02; 95% CI: 0.92–1.14). PP analysis revealed similar results. HT was associated with higher compliance rates than CT and slightly lower than ST. As far as adverse events are concerned, this meta-analysis demonstrated a higher occurrence of adverse events on the group of patients treated with CT when compared with HT. HT and ST showed similar results.ConclusionHT has similar eradication, compliance and adverse event rates when compared to ST, but a better safety profile than the CT.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12941-023-00582-2.