Objective: Helicobacter pylori remains one of the most prevalent bacterial infections globally. While H. pylori eradication reduces gastric cancer risk, increasing antimicrobial resistance (AMR) impairs the effective treatment with major geographic variability. This systematic review summarizes the global epidemiology, mechanisms of resistance, clinical consequences, and emerging strategies to address H. pylori AMR.

Materials and Methods: We systematically searched PubMed, Scopus, and Web of Science for articles published between 2000 and June 2025. Keywords included “Helicobacter pylori”, “antimicrobial resistance”, “clarithromycin”, “metronidazole”, “levofloxacin”, “children”, and “epidemiology”. Inclusion criteria comprised English-language studies in human subjects reporting prevalence, mechanisms, or treatment outcomes related to resistance. Excluded were case reports, animal studies, and small series (<20 patients). Emphasis was placed on multicenter trials, surveillance reports, and systematic reviews.

Results: Analysis of included studies demonstrated that clarithromycin resistance exceeds 20-30% in many regions, particularly East Asia and Southern Europe, undermining traditional triple therapy. Metronidazole resistance is widespread, ranging from 30-70% globally, while levofloxacin resistance shows alarming upward trends. Amoxicillin and tetracycline resistance remain rare, while rifabutin retains activity against multidrug-resistant strains. Pediatric populations exhibit especially high clarithromycin and metronidazole resistance, with pooled prevalence exceeding 35% in some regions, limiting therapeutic options. Molecular mechanisms primarily involve point mutations in 23S rRNA, rdxA/frxA, and gyrA genes, while next-generation sequencing has identified additional candidate loci. Novel strategies, including bismuth-based quadruple therapy, vonoprazan-based dual regimens, and molecular-guided therapy improve outcomes. Adjunctive measures such as probiotics, antimicrobial peptides, and stewardship interventions offer further promise.

Conclusions: H. pylori AMR represents a critical barrier to eradication worldwide. Expanded global surveillance, rapid molecular diagnostics, and personalized therapy are urgently needed. Future research should prioritize pediatric-focused strategies, non-antibiotic alternatives, and equitable access to optimized regimens. Coordinated international action is essential to contain resistance and preserve the benefits of eradication.