Objective To investigate the therapeutic effect of liangxue-jiedu decoction on acute-on-chronic liver failure (ACLF) model mice and its effect on 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 the combined treatment of carbon tetrachloride (CCl₄), lipopolysaccharide (LPS), and D-galactosamine (D-GalN). Biochemical analysis was performed to evaluate liver function indicators including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL). Histopathological examination was conducted to assess liver tissue morphological changes. Quantitative PCR was used to detect the mRNA expression of tumor necrosis factor α (TNFα), interleukin-6 (IL-6), interleukin-1β (IL1-β), and TLR4 in liver tissues. CCK8 assay was used to evaluate the interventional concentration of Liangxue-Jiedu decoction on Raw 264.7 cells. Enzyme-linked immunosorbent assay was used to detect the contents of TNF-α, IL-6 and IL1-β 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 reduced cell necrosis, fibrosis, and inflammatory cell infiltration in liver tissues, and decreased serum levels of ALT, AST and TBIL, as well as mRNA the expression of TNFα, IL-6, IL1-β, and TLR4. Liangxue-Jiedu decoction reduced TLR4/JNK/NF-κB signaling pathway-related protein expression in liver tissues. Furthermore, the in vitro result also showed that Liangxue-Jiedu decoction reduced TNFα, IL-6, IL1-β secretion in macrophage cells, and down-regulated the protein expression of TLR4/JNK/NF-κB signaling pathway. Conclusions Liangxue-Jiedu decoction effectively improved liver function in ACLF mice, which is closely related to the downregulation of the TLR4/JNK/NF-κB pathway.