Exposure of volatile organic compounds (VOCs) towards lung leads to pulmonary dysfunctions and various lung diseases. However, the interaction of VOCs with pulmonary surfactant (PS) that directly comes into contact with inhaled VOCs is unknown. Here, simulated PS extracted from porcine lungs (EPS) was used to study the interaction with BTEX (i.e., benzene, toluene, ethylbenzene, and p-xylene) as representatives of VOCs. Surface pressure-area (it-A) isotherms showed that in the presence of individual BTEX, EPS monolayer's phase conversion from gas to liquid expanded phase was dramatically influenced and its collapse pressure decreased greatly compared to those of EPS alone, which was attributed to the alteration of EPS monolayer's microstructure characterized by atomic force microscopy and Brewster angle microscopy. Solubilization experiments manifested that EPS and its major components (dipalmitoyl phosphatidylcholine, DPPC; bovine serum albumin, BSA) exhibited obvious solubilization effects on individual BTEX. The solubilization capacity followed an order: EPS > DPPC > BSA, which was positively correlated with hydrophobicity of individual BTEX. Synergistic solubilization test unveiled that the mixed phospholipid components were largely responsible for the solubilization capacity of EPS. These findings indicate that VOCs exposure may induce potential pulmonary health risk due to the alteration of gas-liquid interfacial properties of PS.