| Summary: | The emergence of multidrug-resistant <i>H. pylori</i> poses a public healthcare threat, particularly in low- and middle-income countries. Recently, the World Health Organization has classified clarithromycin-resistant <i>H. pylori</i> as high priority in the research and discovery of novel antibiotics. This study was aimed to systematically review the prevalence of primary antibiotic resistance in <i>H. pylori</i> in Southeast Asian countries (SEAC) and to review current studies of antimicrobial peptides against <i>H. pylori</i>. We systematically searched through electronic databases of studies conducted on antimicrobial resistance of <i>H. pylori</i> in SEA countries. Furthermore, we searched articles that conducted studies on antimicrobial peptides, naturally occurring host’s defense molecules, against <i>H. pylori</i>. After a series of screening processes, 15 studies were included in our systematic review. Our analysis revealed that primary resistance of <i>H. pylori</i> to metronidazole, clarithromycin, and levofloxacin were high in SEAC, although the primary resistance to amoxicillin and tetracycline remains low. Multidrug-resistant <i>H. pylori</i> are emerging in SE Asian countries. The antimicrobial peptides show promising antibacterial and antibiofilm activity against drug-resistant <i>H. pylori</i>. The research and discovery of antimicrobial peptides against <i>H. pylori</i> in SEAC will help in limiting the spread of antimicrobial resistance of <i>H. pylori</i>.
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