Objective To assess the efficacy, safety and compliance with dual, triple and quadruple therapy first-line regimens for Helicobacter pylori eradication. Design A systematic review and network meta-analysis (NMA) reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses NMA guidance. Data sources PubMed, Cochrane Library, ProQuest and Scopus were searched until 12 October 2025. Eligibility criteria Randomised controlled trials (RCTs) published in English that measured the eradication rate, adverse events and compliance rates of dual therapy compared with triple or quadruple therapy for H. pylori first-line treatment. Data extraction and synthesis Data extraction and risk-of-bias assessment were performed by two independent reviewers. The data were analysed and represented as pooled ORs. Heterogeneity was assessed using meta-regression and trim-and-fill analyses. Results Pairwise meta-analysis of 56 RCTs showed that dual therapy had no different eradication rates than triple therapy (intention-to-treat (ITT): OR 0.88, 95% CI 0.60 to 1.29; per-protocol (PP): OR 0.76, 95%CI 0.46 to 1.25). Dual therapy outperformed quadruple therapy (OR 1.20, 95%CI 1.04 to 1.39) with fewer adverse events (OR 0.32, 95%CI 0.28 to 0.38) and higher compliance rates (OR: 1.49, 95%CI 1.26 to 1.76). Based on the NMA, RAC-7 has the highest probability of effective treatment for both ITT (P-score=0.9436) and PP (P-score=0.9545). Conclusion Dual therapy represents a promising first-line option, demonstrating comparable efficacy and adverse event rates with higher compliance, although triple therapy showed the highest probability of being the most effective first-line regimen in the NMA, followed by quadruple therapy. Further studies in non-Asian populations, along with resistance-guided treatment approaches, are needed to refine global eradication strategies. © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.