Background: Epigenetics studies heritable or inheritable mechanisms that regulate gene expression rather than altering the DNA sequence. However, no research has investigated the link between TME-related genes (TRGs) and epigenetic-related genes (ERGs) in GC. Methods: A complete review of genomic data was performed to investigate the relationship between the epigenesis tumor microenvironment (TME) and machine learning algorithms in GC. Results: Firstly, TME-related differential expression of genes (DEGs) performed non-negative matrix factorization (NMF) clustering analysis and determined two clusters (C1 and C2). Then, Kaplan–Meier curves for overall survival (OS) and progression-free survival (PFS) rates suggested that cluster C1 predicted a poorer prognosis. The Cox–LASSO regression analysis identified eight hub genes (SRMS,MET,OLFML2B,KIF24,CLDN9,RNF43,NETO2, andPRSS21) to build the TRG prognostic model and nine hub genes (TMPO,SLC25A15,SCRG1,ISL1,SOD3,GAD1,LOXL4,AKR1C2, andMAGEA3) to build the ERG prognostic model. Additionally, the signature’s area under curve (AUC) values, survival rates, C-index scores, and mean squared error (RMS) curves were evaluated against those of previously published signatures, which revealed that the signature identified in this study performed comparably. Meanwhile, based on the IMvigor210 cohort, a statistically significant difference in OS between immunotherapy and risk scores was observed. It was followed by LASSO regression analysis which identified 17 key DEGs and a support vector machine (SVM) model identified 40 significant DEGs, and based on the Venn diagram, eight co-expression genes (ENPP6,VMP1,LY6E,SHISA6,TMEM158,SYT4,IL11, andKLK8) were discovered. Conclusion: The study identified some hub genes that could be useful in predicting prognosis and management in GC.