BACKGROUND AND AIMS: The eradication of reduces the incidence of gastric cancer. However, the efficacy of the widely used triple therapy for eradicating has progressively reduced. This may have resulted from the increase in clarithromycin resistance in recent years. Recent guidelines recommend the use of bismuth quadruple therapy (BQT) as first-line eradication therapy for infection in areas with high (>15%) or unknown clarithromycin resistance. However, the eradication rates of proton pump inhibitor (PPI)-based BQT remain below the required standard. This systematic review aimed to evaluate the use of novel acid suppressant (potassium-competitive acid blocker [P-CAB])-based BQT compared with PPI-based BQT for eradication. METHODS: A systematic review and network meta-analysis were conducted using the PubMed, Cochrane Library, ProQuest, and Scopus databases, along with randomized controlled trials comparing P-CAB-based and PPI-based BQT for eradication. RESULTS: Intention-to-treat analysis showed a pooled risk ratio (RR) of 1.04 (95% confidence interval: 1.02-1.06, I = 0) and per-protocol set analysis yielded an RR of 1.04 (95% confidence interval: 1.01-1.07, I = 0), favoring P-CAB-based BQT with minimal heterogeneity. Seven studies (n = 2222) reported no significant difference in adverse events (RR: 1.06 [0.99-1.14, I = 30.6%]). CONCLUSION: Meta-analysis showed the P-CAB-based BQT had slightly higher efficacy than PPI-based BQT. However, network meta-analysis revealed that vonoprazan-based BQT did not show superiority over esomeprazole-based BQT. Therefore, tailored therapies based on local resistance patterns remain critical considerations in clinical practice.