Among various therapeutic agents, Oncolytic Viruses (OVs) are the most promising anticancer therapeutics because of their tumor-specific targeting and capability to mediate an antitumor immune response. In this review, we will discuss how epigenetic reprogramming of both the host and tumor can facilitate increased sensitivity of tumors to OV therapy. OVs infect tumor cells and modulate epigenetic landscapes, including DNA methylation, histone modifications, and chromatin remodeling, as well as non-coding RNA expression that consequently induces immune responses. These epigenetic changes, including hypermethylation of tumor-associated antigen genes and chromatin accessibility alterations, enhance the immunogenicity of tumors to facilitate recognition by the immune system. Here, we provide a general review addressing this question by discussing the potential benefits of combining OVs with epigenetic drugs to combat resistance and promote treatment efficacy. This information illustrates the importance of personalized OV therapy regarding epigenome in individual profiles and transitions. Still, it extends difficulty in inducing with acquisitions of viral-induced changes globally and making translatable steps by creating cancer-specific predictive treatment models.