Objective To investigate the therapeutic effect of Liangxue-jiedu decoction on acute-on-chronic liver failure (ACLF) model mice and the Toll-like receptor 4 (TLR4) / c-Jun amino terminal kinase ( JNK) / nuclear factor κB (NF-κB) signaling pathway. Methods An ACLF mouse model was established using combined treatment of carbon tetrachloride, lipopolysaccharide, and D-galactosamine. Biochemical analysis was performed to evaluate liver function indicators, including alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Histopathological examination was conducted to assess liver tissue morphological changes. Quantitative PCR was used to detect the mRNA expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, and TLR4 in liver tissues. A CCK8 assay was used to evaluate the optimal interventional concentration of Liangxue-jiedu decoction on Raw 264. 7 cells. Enzymelinked immunosorbent assay was used to detect the contents of TNF-α, IL-6, and IL-1β in the cell supernatant. Protein immunoblotting was performed to measure the expression of TLR4 / JNK/ NF-κB signaling pathway-related proteins,including TLR4, NF-κB, p-ERK1 / 2, ERK1 / 2, p-JNK, and JNK. Results Compared with the ACLF model group, the Liangxue-jiedu decoction-treated group showed reduced cell necrosis, fibrosis, and inflammatory cell infiltration in liver tissues; decreased serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin; and lower expression of TNF-α, IL-6, IL-1β, and TLR4 mRNA. Liangxue-jiedu decoction reduced TLR4 / JNK/ NF-κB signaling pathway-related protein expression in liver tissues. The in vitro result also showed that Liangxue-jiedu decoction reduced TNF-α, IL-6, and IL-1β secretion by macrophage cells and down-regulated the expression of TLR4 / JNK/ NF-κB signaling pathway proteins. Conclusions Liangxue-jiedu decoction effectively improved liver function in ACLF mice in a manner closely related to the downregulation of TLR4 / JNK/ NF-κB pathway proteins.