Objective：To investigate the mechanism by which Notch1 signaling regulates acetyl-para-aminophenol（APAP）-induced liver injury（AILI）via TAK1. Methods：AILI models were constructed on myeloid-specific Notch1 knockout（Notch1^M-KO）and floxed Notch1（Notch1^FL/FL）mice by intraperitoneal injection of APAP. Serum samples of mice were collected for detection of liver function and cytokines by fully automated biochemical analyser and enzyme-linked immunoassay（ELISA），respectively. The pathological damage of liver tissue was observed by HE staining，and the degree of liver tissue damage was evaluated by Suzuki score. Western blot analysis was performed to detect the expression levels of TAK1，phospho -TAK1，p65，phospho -p65，caspase -8，receptor -interacting protein kinase1（RIPK1），and phospho-mixed lineage kinase domain-like protein（MLKL）in the liver tissue. The expressions of CD11b，p-TAK1 and the level of reactive oxygen species（ROS）were observed by immunofluorescence staining. Results：After injected with APAP intraperitoneally in mice，liver histopathological examination suggested increased hepatocyte volume，sinus congestion，and extensive necrosis. Compared with Notch1^FL/FL group，Notch1^{M- KO} mice showed significantly elevated serum alanine aminotransferase（ALT） and aspartate aminotransferase（AST），increased inflammatory factor levels. HE staining showed more pronounced increase in hepatocyte volume，accompanied by extensive necrosis and increased infiltration of inflammatory cells. Additionally，the primary hepatocytes showed higher levels of ROS when assessed using the DCF probe. The expression of p-TAK1 in liver tissue elevated，and the expression of caspase-8 was down-regulated，while the expressions of RIPK1 and p-MLKL were up- regulated. Conclusion：In AILI，myeloid-specific Notch1 knockout activates TAK1 expression，which also decreases caspase-8 levels and promotes the RIPK1-MLKL necroptosis pathway，aggravating the liver injury.