Acute liver failure (ALF) is an acute liver disease with a high mortality rate in clinical practice, characterized histologically by extensive hepatocellular necrosis and massive neutrophil infiltration. However, the role of these abnormally infiltrating neutrophils during ALF development is unclear. Here, in an ALF mouse model, metabolites were identified that promote the formation of neutrophil extracellular traps (NETs) in the liver, subsequently influencing macrophage differentiation and disease progression. ALF occurs with abnormalities in hepatic and intestinal metabolites. Abnormal metabolites (LTD4 and glutathione) can directly, or indirectly via reactive oxygen species, promote NET formation of infiltrating neutrophils, which subsequently regulate macrophages in a pro-inflammatory M1-like state, inducing an amplification of the destructive effects of inflammation. Together, this study provides new insights into the role of NETs in the pathogenesis of ALF. Acute liver failure (ALF) involves liver tissue necrosis and neutrophil infiltration. Increased leukotriene D4 levels disrupt the intestinal barrier, allowing enterobacteria and endotoxin migration to the liver, triggering NETosis. Blood and liver glutathione redox system abnormalities raise reactive oxygen species levels, promoting NETosis. Enhanced NETosis disturbs macrophage balance, increasing pro-inflammatory effects, worsening hepatic pathology, and progressing the disease. image