Epstein-Barr virus (EBV) is a double-stranded DNA virus that was first isolated in 1964 and is a major human tumor virus. It infects over 90% of the global population and is associated with various cancers and autoimmune disorders. EBV employs epigenetic mechanisms to establish long-term latency and interact with its host, contributing to the development and progression of EBV-associated diseases. The virus uses histone modifications, DNA methylation, and microRNA (miRNA) targeting to regulate host-virus interactions, enabling viral persistence and disease progression. The review discusses four key epigenetic regulatory mechanisms that facilitate EBV infection, persistence, and disease development. It also explores how host epigenetic profiles are altered in EBV-associated cancers to understand the precise interactions between EBV and its host. The review highlights the role of EBV in modulating host gene expression through epigenetic regulation, including DNA methylation, histone modifications, and chromatin remodeling. EBV microRNAs also play a critical role in promoting viral persistence by modulating host gene expression and immune evasion. The review further examines the epigenetic hallmarks in EBV-associated cancers, such as nasopharyngeal carcinoma (NPC) and EBV-associated gastric cancers (EBVaGC), where host-virus interactions lead to aberrant methylation, histone modifications, and altered gene expression. These epigenetic changes contribute to the development of cancer by promoting genomic instability, uncontrolled cell division, and resistance to apoptosis. The study provides insights into the complex interplay between EBV and host epigenetic mechanisms, highlighting the importance of understanding these interactions for developing therapeutic strategies against EBV-associated diseases.Epstein-Barr virus (EBV) is a double-stranded DNA virus that was first isolated in 1964 and is a major human tumor virus. It infects over 90% of the global population and is associated with various cancers and autoimmune disorders. EBV employs epigenetic mechanisms to establish long-term latency and interact with its host, contributing to the development and progression of EBV-associated diseases. The virus uses histone modifications, DNA methylation, and microRNA (miRNA) targeting to regulate host-virus interactions, enabling viral persistence and disease progression. The review discusses four key epigenetic regulatory mechanisms that facilitate EBV infection, persistence, and disease development. It also explores how host epigenetic profiles are altered in EBV-associated cancers to understand the precise interactions between EBV and its host. The review highlights the role of EBV in modulating host gene expression through epigenetic regulation, including DNA methylation, histone modifications, and chromatin remodeling. EBV microRNAs also play a critical role in promoting viral persistence by modulating host gene expression and immune evasion. The review further examines the epigenetic hallmarks in EBV-associated cancers, such as nasopharyngeal carcinoma (NPC) and EBV-associated gastric cancers (EBVaGC), where host-virus interactions lead to aberrant methylation, histone modifications, and altered gene expression. These epigenetic changes contribute to the development of cancer by promoting genomic instability, uncontrolled cell division, and resistance to apoptosis. The study provides insights into the complex interplay between EBV and host epigenetic mechanisms, highlighting the importance of understanding these interactions for developing therapeutic strategies against EBV-associated diseases.