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Background and Aims: Acute liver failure (ALF) is an inflammatory process of acute liver cell injury. Mesenchymal stem cells (MSCs) are undifferentiated, primitive cells with antiinflammatory, anti-apoptotic, and multi-directional differentiation abilities. This study aimed to explore the therapeutic mechanism of umbilical cord (U)MSCs in ALF. Methods: Dgalactosamine (D-GalN) combined with lipopolysaccharide (LPS) was used to establish an ALF model. After model establishment, UMSCs were injected via the tail vein. After UMSC transplantation, the number of mouse deaths was monitored every 12 h. A fully automatic biochemical analyzer was used to detect changes in biochemical analysis. Pathological changes was observed by stained with hematoxylin and eosin.The expression of My D88 was detected by immunohistochemical analysis, quantitative reverse transcription, and western blotting. The expression of NF-κB was detected by quantitative reverse transcription, western blotting.The expression of Bcl-2,Bax were detected by quantitative reverse transcription, western blotting.The expression of TNF-α, IL-1β, IL-6 were detected by enzyme-linked immunosorbent assay. Results: The 48-h survival rate of the UMSC-treated group was significantly higher than that of the LPS/D-GalNexposed group. After 24 h of LPS/D-GalN exposure, UMSCs reduced serum alanine aminotransferase and aspartate aminotransferase levels and improved the liver structure. Western blot and real-time fluorescence quantitative nucleic acid amplification analyses showed that UMSCs decreased MyD88 expression, thereby inhibiting LPS/GalN-induced phosphorylation and degradation of inhibitor of nuclear factor (NF)-κB (IκB). Additionally, NF-κB p65 underwent nuclear translocation, inhibiting the production of the inflammatory factors interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and played a protective role in ALF by down-regulating the pro-apoptotic gene Bax and up-regulating the anti-apoptotic gene Bcl-2. In summary, these findings indicate that UMSCs play a protective role in LPS/GalN-induced acute liver injury via inhibition of the MyD88 pathway and subsequent inhibition of NF-κB-mediated cytokine production. Conclusions: Through the above mechanisms, UMSCs can effectively reduce LPS/D-GalN-induced ALF, reduce mouse mortality, and restore damaged liver function and damaged liver tissue.