Pilchard orthomyxovirus (POMV) is an emerging pathogen of concern to the salmon industry in Australia. To explore the molecular events that underpin POMV infection, we challenged Atlantic salmon () post-smolts in seawater via cohabitation. Tissue samples of the head kidney and liver were collected from moribund and surviving individuals and analyzed using transcriptome sequencing. Viral loads were higher in the head kidney compared to the liver, yet the liver presented more upregulated genes. Fish infected with POMV showed a strong innate immune response that included the upregulation of pathogen recognition receptors such as RIG-I and Toll-like receptors as well as the induction of interferon-stimulated genes (). Moribund fish also presented a dramatic induction of pro-inflammatory cytokines, contributing to severe tissue damage and morbidity. An induction of major histocompatibility complex (MHC) class I genes () and markers of T cell-mediated immunity () was observed in both moribund fish and survivors. In addition, differential connectivity analysis showed that three key regulators (, and ) related to cell-mediated immunity had significant differences in connectivity in "clinically healthy" versus "clinically affected" or moribund fish. Collectively, our results show that T cell-mediated immunity plays a central role in the response of Atlantic salmon to the infection with POMV.