Mechanical forces in the respiratory system, including surface tension forces during airway reopening and high transmural pressures, can result in epithelial cell injury, barrier disruption and inflammation. In this study, we investigated if a clinically relevant pharmaceutical agent, Simvastatin, could mitigate mechanically induced injury and inflammation in respiratory epithelia. Pulmonary alveolar epithelial cells (A549) were exposed to either cyclic airway reopening forces or oscillatory transmural pressure in vitro and treated with a wide range of Simvastatin concentrations. Simvastatin induced reversible depolymerization of the actin cytoskeleton and a statistically significant reduction the cell’s elastic modulus. However, Simvastatin treatment did not result in an appreciable change in the cell’s viscoelastic properties. Simvastatin treated cells did exhibit a reduced height-to-width aspect ratio and these changes in cell morphology resulted in a significant decrease in epithelial cell injury during airway reopening. Interestingly, although very high concentrations (25–50 µM) of Simvastatin resulted in dramatically less IL-6 and IL-8 pro-inflammatory cytokine secretion, 2.5 µM Simvastatin did not reduce the total amount of pro-inflammatory cytokines secreted during mechanical stimulation. These results indicate that although Simvastatin treatment may be useful in reducing cell injury during airway reopening, elevated local concentrations of Simvastatin might be needed to reduce mechanically-induced injury and inflammation in respiratory epithelia.