The process of antiviral response is a complex and vast process involving the interplay of multiple signaling pathways, leading to the production of cytokines that coordinate the immune response. Recently, O-GlcNAcylation has been found to play a role in antiviral responses, especially against RNA viruses. Increased glucose uptake or the regulation of key proteins in its pathway following infection happen to induce O-GlcNAcylation. In humoral immunity, O-GlcNAcylation is responsible for the maturity and migration of immune cells to infected sites. Interestingly, these functions are context-dependent and may pose “friend” and/or “foe” effects to the virus as well as the cell/body. In this study, I examine existing knowledge of O-GlcNAcylation and its signaling in relation to glucose metabolism and the coordination of antiviral innate and adaptive immunity for and against viral infection.