Severe sepsis is a complex, multifactorial, and rapidly progressing disease characterized by excessive inflammation and coagulation following bacterial infection. To simultaneously suppress pro-inflammatory and pro-coagulant responses, we genetically engineered a novel fusion protein (MR1007) consisting of an anti-CD14 antibody and the modified second domain of bikunin, and evaluated the potential of MR1007 as an anti-sepsis agent. Suppressive effects of MR1007 on lipopolysaccharide (LPS)-induced inflammatory responses were assessed using peripheral blood mononuclear cells or endothelial cells. Its inhibitory activity against the coagulation factor XIa was assessed using a purified enzyme and a chromogenic substrate. Anticoagulant activity was assessed using human or rabbit plasma. Anti-inflammatory and anti-coagulant effects and/or survival benefits were evaluated in an endotoxemia model and a cecal ligation and puncture model. MR1007 inhibited LPS-induced cytokine production in peripheral blood mononuclear cells and endothelial cells, inhibited factor XIa, and exhibited anticoagulant activity. In an endotoxemia model, 0.3–3 mg/kg MR1007 suppressed pro-inflammatory and pro-coagulant responses in a dose-dependent manner; at a dose of 3 mg/kg, the protein improved survival even when administered 8 h after the LPS injection. In addition, 10 mg/kg MR1007 administered 2 h post cecal ligation and puncture improved survival. However, MR1007 administered at doses up to 30 mg/kg did not increase ear bleeding time or bacterial counts in the cecal ligation and puncture model. Thus, simultaneous targeting of CD14 and factor XIa improves survival in the rabbit endotoxemia and sepsis models and represents a promising approach for the treatment of severe sepsis.