Sepsis is recognized as the acute systemic inflammatory response to severe infection. It is main cause of multiple organ system dysfunction and even organ failure. Long non-coding RNA X inactivate-specific transcript (XIST) is implicated in multiple inflammatory diseases. The aim of present work was to investigate the precise mechanism of XIST underlying sepsis-induced acute liver injury. Rats were underwent cecal ligation and puncture (CLP) to establish sepsis-induced the animal models of acute liver injury. Hematoxylin and eosin (H&E) staining was performed to observe pathological alterations. Corresponding commercial assay kits were employed to analyze the levels of inflammatory cytokines and oxidative stress. Western blot and reverse transcriptional quantitative PCR (RT-qPCR) were performed to determine the expression of proteins and target genes. Finally, TUNEL and CCK-8 assays were performed to test apoptosis rate and cell viability, respectively. In our study, XIST and BRD4 were highly expressed in serum of patients with sepsis-induced acute liver injury. XIST knockdown ameliorated sepsis-induced acute liver injury and inhibited inflammation, oxidative stress, and cell apoptosis in sepsis-induced acute liver injury rats. Interestingly, XIST knockdown downregulated the expression of BRD4, and BRD4 overexpression abolished the impacts of XIST knockdown on inflammation, oxidative stress, and apoptosis of that LPS-induced Kupffer cells. We conclude that lncRNA XIST silencing protects against sepsis-induced acute liver injury via inhibition of the BRD4 expression. Therefore, XIST may be a biomarker for sepsis diagnosis and treatment.