Abstract: In order to investigate the disease resistance and metabolic regulatory network of Micropterus salmoides to M. salmoides rhabdovirus (MSRV), uncover the immunomolecular mechanism of its disease resistance, and provide genetic data references for subsequent molecular biology investigation of M. salmoides, we used the Illumina NovaSeq 6000 sequencing platform to analyze the transcriptome sequencing of liver tissues from susceptible group, disease-resistant group and control group of M. salmoides infected with MSRV. Functional annotation of obtained genes reveals that the annotated differentially expressed genes were mainly associated with functions such as cellular process, cell, binding and catalytic activity, etc. The KEGG pathway enrichment analysis indicates that the differentially expressed genes with high expression levels in M. salmoides liver tissue with MSRV infection were enriched in metabolic pathways, including drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450, proteasome, ascorbate and aldarate metabolism, fatty acid degradation, as well as other metabolic processes. Further screening of immune-related genes for pathway analysis shows that the main pathways associated with the immune response against MSRV were NOD-like receptor signaling pathway, C-type lectireceptor signaling pathway, cytosolic DNA-sensing pathway, Toll-like receptor signaling pathway, RIG-I-like receptor signaling pathway, etc. Finally, we verified the consistency of the differential gene trends with the results of transcriptome sequencing analysis by qRT-PCR, demonstrating the reliability of the transcriptome data. The differential genes and regulatory pathways identified in this study will provide a theoretical basis for research on the molecular mechanism of M. salmoides immunity against MSRV as well as disease prevention and control.