Helicobacter pylori infection is one of the most common gastric pathogens; however, the molecular mechanisms driving its progression to gastric cancer remain poorly understood. This study aimed to identify the key transcriptomic drivers and therapeutic targets of H. pylori–associated gastric cancer through an integrative transcriptomic analysis. This analysis integrates microarray and RNA-seq datasets to identify significant differentially expressed genes (DEGs) involved in the progression of H. pylori–associated gastric cancer. In addition to independent analyses, data were integrated using ComBat to detect consistent expression patterns of hub genes. This approach revealed distinct clustering patterns and stage-specific transcriptional changes in common DEGs across disease progression, including H. pylori infection, gastritis, atrophy, and gastric cancer. Genes such as TPX2, MKI67, EXO1, and CTHRC1 exhibited progressive upregulation from infection to cancer, highlighting involvement in cell cycle regulation, DNA repair, and extracellular matrix remodeling. These findings provide insights into molecular shifts linking inflammation-driven infection to malignancy. Furthermore, network analysis identified hub genes, including CXCL1, CCL20, IL12B, and STAT4, which are enriched in immune pathways such as chemotaxis, leukocyte migration, and cytokine signaling. This emphasizes their role in immune dysregulation and tumor development. Expression profiling demonstrated the upregulation of hub genes in gastric cancer and stage-specific changes correlating with disease progression. Finally, drug–gene interaction analysis identified therapeutic opportunities, with hub genes interacting with approved drugs like abatacept and zoledronic acid, as well as developmental drugs such as adjuvant and relapladib. These findings highlight the key role of these hub genes as biomarkers and therapeutic targets, providing a foundation for advancing precision medicine in H. pylori–associated gastric cancer. Overall, this study paves the way for advancing precision medicine in H. pylori–associated gastric cancer by providing insights into the development of early detection biomarkers, risk stratification, and targeted therapies. This supports the clinical translation of precision medicine strategies in H. pylori–associated gastric cancer.