Innate immunity is an important component of the immune system and serves as the first line of defense for the host against the invasion of foreign pathogens. Viperin (RSAD2), a core member of the interferon-stimulated gene (ISG) family, plays a key role in innate immunity through direct inhibition of viral replication and modulation of the host immune-metabolic network. The intracellular expression of Viperin rises markedly after viral infection or interferon-induced induction, showing a wide range of antiviral activities. In recent years, the versatility of Viperin in viral infections, autoimmune diseases, and tumor immune metabolism has been gradually revealed. Here, we summarize and discuss the gene regulatory network, molecular functions, and multi-dimensional roles of Viperin in diseases to provide a theoretical basis for the development of broad-spectrum antiviral strategies and immunometabolic therapies based on Viperin.