Sepsis is one of the systemic inflammatory responses, and it can cause acute respiratory distress syndrome (ARDS). Mechanical ventilation (MV) is one of the best treatments in patients with sepsis related to ARDS. However, mechanical ventilation itself can cause lung injury through various mechanisms. In this study, we applied mouse cecal ligation and puncture (CLP) model of sepsis with subsequent injurious ventilation to determine if sepsis could affect the development of ventilator-induced lung injury (VILI). To evaluate lung injury caused by sepsis, mild, moderate, and severe CLPs were induced. To evaluate lung injury caused by MV with or without sepsis, tidal volume (7 mL/kg, 10 mL/kg, or 24 mL/kg) was maintained for 3 h with or without septic insult (mild sepsis for 72 h). Lung compliance was then determined and biochemical evaluations were performed. Results showed that lung compliance was lower in the severe sepsis group compared to that in the mild or moderate sepsis group. MV alone decreased lung compliance in a tidal volume dependent manner. Both CLP and VILI groups showed significant decrease in lung compliance and increase in total cell count upon bronchoalveolar lavage fluid. These results confirm that ventilation can affect lung injury in mouse sepsis model.