Edwardsiella ictaluri, an important pathogen in aquaculture, can cause severe liver damage and metabolic disorders in fish. In this study, we investigated the effect of dietary oligochitosan on hybrid grouper infected with E. ictaluri. Growth performance parameters showed that E. ictaluri infection significantly reduced the weight gain rate, body length, and survival rate of grouper, which was significantly ameliorated by oligochitosan, as well as significantly increased the hepatopancreas somatic indice. Histopathological and TUNEL analyses showed that E. ictaluri infection resulted in severe liver injury and hepatocyte apoptosis, which were significantly attenuated by oligochitosan. Biochemical analysis showed that E. ictaluri infection increased the activities of glutamate pyruvate transaminase (GPT), catalase (CAT), and glutathione peroxidase (GSH-Px), while oligochitosan supplementation decreased these enzymatic activities. Transcriptomics analysis identified intergroup differentially expressed genes between E. ictaluri infection and oligochitosan supplementation that were significantly enriched in pathways associated with protein processing, steroid biosynthesis, and immune response. Quantitative analysis of immune-related gene expression showed that E. ictaluri infection significantly upregulated interleukin-6 (IL-6) and interleukin-8 (IL-8) while downregulating the nuclear factor kappa B P65 subunit (NF-κB P65) and interleukin-10 (IL-10), effects that were effectively modulated by dietary oligochitosan supplementation. Metabolomics analysis further revealed that E. ictaluri infection disrupted hepatic metabolic profiles, particularly affecting lipid and amino acid metabolism, alterations that were effectively counteracted by oligochitosan. Transcriptomic and metabolomic correlation analyses emphasized the coordinated regulation of key genes and metabolites involved in amino acid and lipid metabolism, suggesting that oligochitosan supplementation restores hepatic metabolic homeostasis and supports liver function. Overall, this study demonstrated that E. ictaluri infection jeopardizes grouper health by impairing growth performance, inducing liver damage, and disrupting the immune-metabolic network, and that oligochitosan intervention was effective in alleviating these pathological processes.