Objective The aim of this study was designed to investigate the effect of Astragaloside IV on sepsis and its immunological mechanism. This study will provide a basis for the theoretical foundation of anti-sepsis immunotherapy of Astragalus. Methods CLP(Cecal ligation and puncture) model was established to investigated the anti-septic potential and reveal its underlying mechanisms, the mice with CLP were divide into five groups including sham group, model group, Astragaloside IV group, Anti-CD45 Ab group and Astragaloside II+Anti-CD45 Ab group. Lung injury in sepsis mice was assessed by H&E staining. The percentage of Th1 cells(CD4+IFN-γ+) were detected by flow cytometry. The mRNA expression of Th1 cytokine and transcript factor T-bet were examined by q-PCR analysis. Results Compared with model group, treatment of Astragaloside IV can markedly improve the survival rate and reduce inflammatory lung injury in sepsis mice. However, anti-CD45 Ab treatment intensely blocked anti-septic effect including the enhanced survival rate and lung injure, which induced by Astragaloside IV. Furthermore, expression of Th1 cells(CD4+IFN-γ+) and Th1 cells related gene (IL-2、T-bet、STAT1、STAT4) mRNA expression were markedly increased in Astragaloside IV group comparison with model group. Whereas, the percentage of Th1 cells and Th1 cells related gene were significantly decreased in Astragaloside IV + Anti-CD45 Ab group. Conclusion Astragaloside IV might promote Th1 cell-mediated immune response in sepsis through CD45 protein tyrosine phosphatase activity. This mechanism will provide a basis for the clinical application of Astragalus in treating sepsis.