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Abstract: The plausibility of human exposure to particulate matter (PM) has witnessed an increase within the last several years. PM of different sizes has been discovered in the atmosphere given the role of dust transport in weather and climate composition. As a regulator, the lung epithelium orchestrates the innate response to local damage. Herein, we developed a lung epithelium-ona-chip platform consisting of easily moldable polydimethylsiloxane layers along with a thin, flexible, and transparent ionic liquid-based poly(hydroxyethyl) methacrylate gel membrane. The epithelium was formed through the culture of human lung epithelial cells (Calu-3) on this membrane. The mechanical stress at the air–liquid interface during inhalation/exhalation was recapitulated using an Arduino-based servo motor system, which applied a uniaxial tensile strength from the two sides of the chip with 10% strain and a frequency of 0.2 Hz. Subsequently, the administration of silica nanoparticles (PM0.5) with an average size of 463 nm to the on-chip platform under static, dynamic, and dynamic + mechanical stress (DMS) conditions demonstrated the effect of environmental pollutants on lung epithelium. The viability and release of lactate dehydrogenase were determined along with proinflammatory response through the quantification of tumor necrosis factor-α, which indicated alterations in the epithelium.