Antibiotic-resistant Helicobacter pylori infection has emerged as a major global public health concern, significantly compromising the efficacy of standard eradication therapies. The increasing prevalence of resistance to clarithromycin, metronidazole, and levofloxacin has been associated with higher rates of treatment failure, persistent gastritis, recurrent peptic ulcer disease, and an elevated risk of gastric malignancies. Molecular mechanisms driving resistance include point mutations in bacterial genes (23S rRNA, rdxA, frxA, gyrA) and biofilm formation, which collectively reduce antibiotic susceptibility. Regional variations in resistance prevalence highlight the importance of localized surveillance and tailored therapeutic strategies. Advances in molecular diagnostics, personalized treatment regimens, and bismuth-based quadruple therapies have improved eradication outcomes in resistant infections. This review emphasizes the urgent need for integrated clinical, molecular, and public health approaches to mitigate the spread of antibiotic-resistant H. pylori and improve global infection control.