Renibacterium salmoninarum is a Gram-positive pathogen that causes Bacterial Kidney Disease (BKD) in wild and cultured marine fish including salmonids, and non-salmonids like lumpfish (Cyclopterus lumpus) which is utilized as a living pest remover to biocontrol the sea lice (Lepeophtheirus salmonis) infestations in Atlantic salmon (Salmo salar) sea cages. Lumpfish susceptibility to R. salmoninarum has been reported recently. However, the transcriptome response of lumpfish to this immune-suppressive pathogen remains unknown. To profile the global gene expression response of lumpfish to R. salmoninarum at early and chronic infection stages, fish were intraperitoneally injected with either a high dose R. salmoninarum (1×109 cells dose-1) or PBS (control), and head kidney samples were collected at 28 and 98 days post infection (dpi) for RNA sequencing. In addition, blood samples taken at 14, 28, 42, 56, 70, and 98 days post-infection were used for the lysozyme and indirect ELISA assays. Transcriptomic profiling identified 2019 and 147 differentially expressed genes (DEGs) in the 28 and 98 dpi, respectively. Pathogen recognition, inflammatory cytokines, immunoregulatory response, iron regulation, and interferon-induced effectors related genes were differentially regulated at 28 dpi, whereas cell-mediated immunity-related genes showed differential regulation at 98 dpi. The pathway enrichment analyses reveal several innate and adaptive immune pathways (i.e., NFKB, MAPK, and JAK-STAT signaling pathways, TNF-α dependent killing pathways, MHC-dependent pathways) that were dysregulated in response to R. salmoninarum infection at early and chronic infection stages. Lysozyme activity and pathogen specific IgM titers of the infected fish coincided with the immune suppressive nature of the R. salmoninarum infection. In summary, R. salmoninarum causes immune suppression at early infection, whereas lumpfish induce cell-mediated immune response at chronic infection. The present study provides a more complete depiction of diverse immune mechanisms dysregulated by R. salmoninarum in lumpfish and open avenue to develop immune prophylactic tools to combat BKD.