DNA methylation has an important role in Helicobacter pylori (H. pylori)-induced gastric cancer (GC) processes and development. The aim of this study was to search genome-scale epigenetic modifications for studying pathogenesis of H. pylori-induced GC, and to find factors and powerful signature related to survival and prognosis. In this study, we conducted a comprehensive analysis of DNA methylation and gene expression profiles in the Gene Expression Omnibus (GEO), to identified differentially expressed genes (DEGs) and differentially methylated genes (DMGs). Functional enrichment analysis of the screened genes was performed, and a protein-protein interaction network was constructed. The TCGA DNA methylation databases and 55 H. pylori-infected GC cases of GEO RNA sequencing (GSE62254) were utilized for prognostic value validation of hub genes. Finally, a prognosis-related risk signature was identified by a series of bioinformatics analysis for H. pylori-induced GC patients. Totally, 161 DMGs were identified. Pathway analysis showed that all MDEGs mainly associated with Ras signaling pathway, renal cell carcinoma, mitogen-activated protein kinase signaling pathway. Five hub genes including CACNB2, GNB4, GRIN2A, MEF2C, and PREX1 were screened as independent prognostic factors in H. pylori-induced GC patients. Two-gene (CACNB2 and MEF2C) risk signature was constructed for predicting the overall survival of H. pylori-induced GC patients. Our study indicated possible MDEGs and pathways in H. pylori-induced GC by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of H. pylori-induced GC. Hub genes might serve as aberrantly methylation-based biomarkers for clinical diagnostic and prognostic evaluation of H. pylori-induced GC.