As the global human population continues to increase and become more industrialized, the need for safe, secure, and sustainable protein production is critical. One sector of particular importance is seafood production, where capture fishery and aquaculture industries provide 15–20% of the global protein supply. However, fish production can be severely affected by diseases. Notably, viral hemorrhagic septicemia, caused by the viral hemorrhagic septicemia virus (VHSv; Rhabdoviridae), may be one of the most devastating viral diseases of fishes worldwide. We explored the ecology and epidemiology of VHSv using an ecological niche modeling approach to identify vulnerable disease-free regions. Results showed an impressive ecological plasticity of VHSv. The virus was found in > 140 fish species in marine and freshwater ecosystems, with high diversity of lineages in Eurasia. Sub-genotypes from marine and fresh waters were ecologically similar, suggesting broad ecological niches, rather than rapid evolutive adaptation to novel environments. Ecological niche models predicted that VHSv may have favorable physical (e.g., temperature, runoff), chemical (e.g., salinity, pH, phosphate), and biotic (i.e., chlorophyll) conditions for establishing into areas with important fish industries that, so far, are believed to be disease-free (i.e., freshwater and marine ecosystems of Africa, Latin America, Australia, and inland China). The model and our review suggest fish species from the Perciformes, Salmoniformes, and Gadiformes orders are likely to be infected with VHSv in novel regions as the virus expands its range to areas predicted to be at risk. In conclusion, VHSv remains an emerging disease threat to global food security and aquatic biodiversity.