The dysregulated cytokine metabolism and activity are crucial to the development of fulminant hepatic failure (FHF), and many different cytokines have been identified. However, the precise gene expression profile and their interactions association with FHF are yet to be further elucidated. In this study, we detected the digital gene expression profile (DGEP) by high-throughput sequencing in normal and FHF mouse liver, and the candidate genes and potential targets for FHF therapy were verified. And the FHF mouse model was induced by D-Galactosamine (GalN)/lipopolysaccharide (LPS). Totally 12727 genes were detected, and 3551 differentially expressed genes (DEGs) were obtained from RNA-seq data in FHF mouse liver. In FHF mouse liver, many of those DEGs were identified as differentially expressed in metabolic process, biosynthetic process, response to stimulus and response to stress, etc. Similarly, pathway enrichment analysis in FHF mouse liver showed that many significantly DEGs were also enriched in metabolic pathways, apoptosis, chemokine signaling pathways, etc. Considering the important role of nuclear factor-kappa B (NF-κB) in metabolic regulation and delicate balance between cell survival and death, several DEGs involved in NF-κB pathway were selected for experimental validation. As compared to normal control, NF-κBp65 and its inhibitory protein IκBα were both significantly increased, and NF-κB targeted genes including tumor necrosis factor α(TNFα), inducible nitric oxide synthase (iNOS), interleukin-1β, chemokines CCL3 and CCL4 were also increased in hepatic tissues of FHF. In addition, after NF-κB was successfully pre-blocked, there were significant alteration of hepatic pathological damage and mortality of FHF mouse model. This study provides the globe gene expression profile of FHF mouse liver, and demonstrates the possibility of NF-κB gene as a potential therapeutic target for FHF.