Background: Sepsis, often triggered by infection, is associated with severe coagulopathy and high mortality. Tissue factor (TF) plays a key role in both coagulation and inflammation during sepsis. The role of TREM2 (Triggering Receptor Expressed on Myeloid cells 2) in sepsis remains unclear, despite its emerging significance in regulating macrophage function. Methods: In vitro, RAW264.7 cells were stimulated with lipopolysaccharide (LPS) to establish a sepsis model, with four groups: Negative Control (NC), NC + LPS, TREM2, and TREM2 + LPS. In vivo, mice were assigned to Sham, TREM2, Cecal Ligation and Puncture (CLP), CLP + NC, and CLP + TREM2 groups. Inflammatory cytokines, coagulation factors, and signaling pathways were assessed. Results: TREM2 overexpression improved survival, reduced lung inflammation, and alleviated coagulopathy in mice. It increased platelet counts and reduced fibrin deposition. TREM2 inhibited TF release from macrophages by suppressing the AKT-mTOR pathway, modulating the inflammatory response. Conclusions: TREM2 plays a protective role in sepsis-associated coagulopathy and may serve as a potential therapeutic target to improve clinical outcomes in sepsis patients.