Background Antimicrobial resistance of H. pylori can lead to treatment failure. Importantly, several studies have reported on heteroresistance, i.e. the presence of resistant and susceptible H. pylori populations in the same sample and/or a difference in the susceptibility patterns between biopsy samples. This meta-analysis aims to provide comprehensive data on the prevalence of metronidazole and clarithromycin heteroresistance and the approaches to their detection. Material and methods A systematic review was performed after the search of MEDLINE, Scopus and Web of Science. The study outcomes were the weighted pooled prevalence of heteroresistance to clarithromycin and metronidazole in H. pylori positive samples and/or isolates with a subanalysis by continent. Results A total of 22 studies that had investigated 3852 H. pylori positive patients were included in the meta-analysis. Heteroresistance to clarithromycin was reported in 20 studies, with a weighted pooled prevalence of 6.8% (95% CI 5.1–8.6; 3654 H. pylori positive patients; the substantial heterogeneity I2 = 55.6%). Heteroresistance to metronidazole was reported in 12 studies, with a weighted pooled prevalence of 13.8% (95% CI 8.9–18.6; 1670 H. pylori positive patients; the substantial heterogeneity I2 = 60.9%). The weighted pooled prevalence of clarithromycin heteroresistance was similar in Asia and Europe (p = 0.174584), however, metronidazole heteroresistance was detected more often in Europe (p < 0.00001). Clarithromycin heteroresistance was detected more often by phenotype rather than by using genotyping methods (12 vs 8 studies), whereas heteroresistance to metronidazole was detected only by phenotype. Conclusion The prevalence of heteroresistance to clarithromycin and/or metronidazole is not negligible and can be detected in approximately 7 and 14% of H. pylori positive samples, respectively. These findings highlight the need to raise the awareness of gastroenterologists and microbiologists to the heteroresistance to clarithromycin and metronidazole in patients with a H. pylori infection.