Viruses continue to pose a public health threat raising the need for effective management strategies. Currently existing antiviral therapeutics are often specific to only a single viral species, and resistance to the therapeutic can often arise, and therefore new therapeutics are needed. The C. elegans-Orsay virus system offers a powerful platform for studying RNA virus–host interactions that could ultimately lead to novel targets for antiviral therapy. The relative simplicity of C. elegans, the well-established experimental tools, and its extensive evolutionary conservation of genes and pathways with mammals are key features of this model. Orsay virus, a bisegmented positive sense RNA virus, is a natural pathogen of C. elegans. Orsay virus infection can be studied in a multicellular organismal context, overcoming some of the limitations inherent to tissue culture-based systems. Moreover, compared to mice, the rapid generation time of C. elegans enables robust and facile forward genetics. This review aims to summarize studies that have laid the foundation for the C. elegans-Orsay virus experimental system, experimental tools, and key examples of C. elegans host factors that impact Orsay virus infection that have evolutionarily conserved function in mammalian virus infection.