Objective To study the protective effect of TSP-1 knockout on acute liver injury induced by carbon tetrachloride in mice. Methods Sixteen C57 BL/6 J mice and eight TSP-1 gene knockout mice were selected for the study. The C57 BL/6 J mice were divided into two groups, WT group and WT+CCl4 group, while the TSP-1 gene knockout mice were grouped as TSP-1-/-+CCl4 group. The WT+CCl4 and TSP-1-/-+CCl4 groups received intraperitoneal injection of 0.5 mL CCl4+9.5 mL/kg olive oil to establish an acute liver injury model, whereas the WT group was given an intraperitoneal injection of 10 mL/kg olive oil as the control. The extent of liver damage and inflammatory response in each group of mice was observed through HE staining and measurement of serum levels of ALT, AST, IL-6, and TNF-α. Additionally, the content of MDA and GSH in liver tissues was determined, and apoptosis was detected by immunohistochemistry and TUNEL staining. Results Knockout of TSP-1 significantly ameliorated acute liver injury induced by CCl4, as evidenced by decreased serum levels of AST, ALT, IL-6, and TNF-α, reduced hepatocyte necrosis, decreased MDA content, increased GSH content, decreased apoptosis, and downregulation of caspase-3 expression in liver tissues. Conclusion Knockout of TSP-1 exerts a marked protective effect against CCl4-induced acute liver injury in mice, possibly through its involvement in the inhibition of inflammation, oxidative stress, and apoptosis. [ABSTRACT FROM AUTHOR]