Herbivorous insects tolerate chemical variation in their host plant diet by modulating several traits. Insect immune response is one trait that plays a crucial role in maintaining fitness but can be heavily influenced by variation in host plant quality. An important question is how the use of different host plants affects the ability of herbivorous insects to resist viral pathogens. Furthermore, the transcriptional changes associated with this interaction of diet and viral pathogens remain understudied. The Melissa blue butterfly (Lycaeides melissa) has colonized the exotic legume Medicago sativa as a larval host within the past 200 years. Here we study the interplay between the effects of host plant variation and viral infection on larval immune responses and global gene expression. We measured immune strength in response to infection by the Junonia coenia densovirus (JcDV) and performed transcriptional sequencing of L. melissa larvae exposed to different viral and host plant treatments. Our results demonstrate that viral infection caused total phenoloxidase (total PO) to increase and viral infection and host plant interactively affected total PO such that for infected larvae, total PO was significantly higher for larvae consuming the native host plant. Additionally, larvae differentially expressed hundredgenes in response to host plant treatment, but with minimal changes in gene expression in response to viral infection. These results demonstrate that in herbivorous insects, diet can alter both physiological and transcriptional responses relevant to viral infection, emphasizing the importance of considering immune and detoxification mechanisms into models of evolution of host range in insects.