Previous studies suggested that diets containing high levels of histamine influenced digestive system of aquatic animals. In addition, the exogenous histamine was first detoxified by diamine oxidase in the intestine, while the rest of histamine was further detoxified in the liver. Thus, based on the evidence from the previous studies, we hypothesized that high levels of histamine may lead to damage on liver of the aquatic animals. Here, in current attempt, we sought to investigate the toxic effect of histamine on yellow catfish (Pelteobagrus fulvidraco) liver physiology and pathogenesis. In the present study, yellow catfish were fed for 56 days on diets supplemented with 1000 mg kg−1 histamine (His) or a basal diet as the control group (Con). A significant change on the morphology of the intestine and liver was observed, followed with an induction of serum activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Furthermore, the transcriptomic analysis was performed to gain an overview of the gene expression profile in liver between control and histamine supplemented groups. Through the bioinformatics analysis, 431 differentially expressed genes were identified. Among these genes, Gene Ontology enrichment analysis (GO) suggests that immune-related genes are significantly dysregulated. In addition, TNF signaling pathway is enriched in Kyoto Encyclopedia of Genes and Genomes analysis (KEGG), and is also the dominant pathway in immune system, suggesting that the inflammatory response and apoptosis of hepatocytes are induced by exogenous histamine.