Antibiotic-resistant Helicobacter pylori is a major cause of severe gastric conditions such as ulcers and gastric cancer, with limited treatment options due to the rise of multidrug-resistant strains. This study aims to identify novel drug targets within antimicrobial resistance (AMR) genes and evaluate potential therapeutic candidates using computational and experimental approaches. AMR genes in H. pylori were identified using RAST and their essentiality, metabolic pathways, and druggability. Localization, protein family, and functional annotations were performed using QuickGO and Pfam, while Cytoscape was used for protein interaction analysis and identification of hub proteins. Ddl was selected as the target protein for further study among the AMR genes. Using the PASS tool, two phenolic compounds were identified as potential inhibitors of Ddl, and their interaction potency was confirmed through molecular docking studies. In-vitro experiments demonstrated that α-mangostin significantly attenuated H. pylori-mediated inflammatory responses in the gastric environment. Notably, α-mangostin induced the mitochondrial-mediated intrinsic apoptotic pathway in gastric epithelial cells, offering new insights into its therapeutic potential. This study identified Ddl as a promising drug target among AMR genes in H. pylori and highlighted phenolic compounds, particularly α-mangostin, as potential inhibitors. These findings contribute to the development of novel anti-H. pylori therapies address the growing challenge of antibiotic resistance and pave the way for future research into effective treatments for H. pylori infections.