Background It was confirmed that alveolar hypercoagulation and fibrinolytic inhibition were associated with refractory hypoxemia in acute respiratory distress syndrome (ARDS), and NF-κB pathway was involved in this process. The purpose of the present study is to explore the effects and relevant mechanisms exerted by NEMO-binding domain peptide (NBDP) to alleviate alveolar hypercoagulation and fibrinolytic inhibition aroused by lipopolysaccharide in ARDS mice. Materials and Methods Adult male BALB/c mice inhaled lipopolysaccharide (LPS, mg/L) to induce ARDS. 30 minutes before LPS administration, we treated the mice with increasing concentrations of intratracheally inhaled NBDP or saline aerosol. Six hours after LPS treatment, bronchoalveolar lavage fluids (BALF) were collected and then all mice were executed. We checked coagulation and fibrinolysis associated factors in lung tissues and in BALF as well. We simultaneously observed the activation of NF-κB signaling pathway as well. Results NBDP pretreatment dose-dependently inhibited either the expressions of tissue factor (TF) and plasminogen activator inhibitor (PAI) 1 in lung tissues or the secretions of TF, PAI-1, thrombin-antithrombin complex (TAT) and promoted activated protein C (APC) secretion in BALF induced by LPS. LPS-induced high expression of pulmonary procollagen peptide type Ⅲ (PⅢP) was also declined by NBDP pretreatment in dose-dependent manner. Western blotting showed that NBDP pretreatment obviously attenuated LPS-induced IKKα/β, Iκα and NF-κB p65 activation. LPS-induced p65 DNA binding activity was inhibited by NBDP pretreatment either. We also noticed NBDP protected mice against LPS-induced lung injury in a dose-dependent manner. Conclusions Our experimental findings demonstrate that NBDP dose-dependently ameliorated LPS-induced alveolar hypercoagulation and fibrinolytic inhibition through inhibiting NF-κB signaling pathway. NBDP is expected to be a new therapeutic target to correct the abnormalities of alveolar coagulation and fibrinolysis in ARDS.