Abstract Background The occurrence of antibiotic‐resistant strains has been rapidly increasing due to the wide use of antibiotics. To evaluate the current effects of antibiotic resistance on Helicobacter pylori eradication efficacy, we conducted this systematic review and meta‐analysis. Methods Literature searches were conducted in the following databases: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Statistical analysis was performed using STATA version 12.0 (StataCorp LP, College Station, TX, USA). Results A total of 120 studies, including 28 707 patients, were assessed. Only first‐line therapy was considered. The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to clarithromycin was 0.682 (95% CI: 0.636‐0.731). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to metronidazole was 0.843 (95% CI: 0.810‐0.877). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to levofloxacin was 0.794 (95% CI: 0.669‐0.941). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to dual clarithromycin and metronidazole was 0.674 (95% CI: 0.590‐0.770). Conclusion Antibiotic resistance causes a decrease in the eradication rate of H pylori today. Quadruple concomitant therapy may overcome the declining H pylori eradication rate caused by metronidazole‐only resistance.