Channel catfish (Ictalurus punctatus) are an important global aquaculture species. To explore gene expression patterns and identify adaptive molecular mechanisms in catfish during salinity stress, we performed growth comparison and comparative transcriptome sequencing on liver tissue. Our study revealed that salinity stress has a significant impact on the growth, survival, and antioxidant system of channel catfish. 927 and 1356 significant DEGs were identified in L vs. C group and H vs. C group. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses suggested that both high and low salinity stress affected gene expression related to oxygen carrier activity, hemoglobin complex, and oxygen transport pathways, and also amino acid metabolism, immune responses, and energy and fatty acid metabolism in catfish. Among mechanisms, amino acid metabolism genes were significantly up-regulated in the low salt stress group, immune response genes were significantly up-regulated in the high salt stress group, and fatty acid metabolism genes were significantly up-regulated in both groups. These results provided a platform for unraveling steady-state regulatory mechanisms in channel catfish under salinity stress, and may limit the impact of extreme salinity changes on catfish during aquaculture practices.