Insect immune response plays a crucial role in how external threats influence overall fitness through life history traits. An understudied question is how the use of different host plants might affect the ability of herbivorous insects to resist viral pathogens. The Melissa blue butterfly (Lycaeides melissa) has colonized the exotic legume Medicago sativa as a larval host within the past 200 years. Here we investigate how novel host plant use affects the immune response of L. melissa when infected with the lepidopteran virus, Junonia coenia densovirus (JcDV). We measured immune strength in response to JcDV in two ways: 1) direct measurement of phenoloxidase activity and melanization, and 2) transcriptional sequencing of individuals exposed to different viral and host plant treatments. Viral infection caused total phenoloxidase (total PO) to increase. We detected an interaction between viral infection and host plant for total PO: for control larvae, host plant use had no effect on total PO, whereas for infected larvae, total PO was significantly higher for larvae consuming the native host. Within the exotic host plant treatment, few genes were differentially regulated due to viral infection. Approximately two times more genes were differentially regulated in response to infection for larvae eating the native or exotic host, with differential expression of few putative immune genes. These results demonstrate that consumption of a novel host plant can alter both physiological and transcriptional responses to infection, emphasizing the importance of understanding diet when studying the molecular basis of immune function.