Pulmonary administration is widely used for the treatment of lung diseases. The interaction between drug molecules and pulmonary surfactants affects the efficacy of the drug directly. The location and distribution of drug molecules in a model pulmonary surfactant monolayer under different surface pressures can provide vivid information on the interaction between drug molecules and pulmonary surfactants during the pulmonary administration. Ketoprofen is a nonsteroidal anti-inflammatory drug for pulmonary administration. The effect of ketoprofen molecules on the lipid monolayer containing 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-glycerol (DPPG) is studied by surface pressure (pi)-area (A) isotherms and compressibility modulus (C-s(-1))-surface pressure (pi) isotherms. The location and distribution of ketoprofen molecules in a lipid monolayer under different surface pressures are explored by surface tension, density profile, radial distribution function (RDF), and the potential of mean force (PMF) simulated by molecular dynamics (MD) simulation. The introduction of ketoprofen molecules affects the properties of DPPC/DPPG monolayers and the location and distribution of ketoprofen molecules in monolayers with various surface pressures. The existence of ketoprofen molecules hinders the formation of liquid-condensed (LC) films and decreases the compressibility of DPPC/DPPG monolayers. The location and distribution of ketoprofen molecules in the lipid monolayer are affected by cation-pi interaction between the choline group of lipids and the benzene ring of ketoprofen, the steric hindrance of the lipid head groups, and the hydrophobicity of ketoprofen molecule itself, comprehensively. The contact state of lipid head group with water is determined by surface pressure, which affects the interaction between drug molecules and lipids and further dominates the location and distribution of ketoprofen in the lipid monolayer. This work confirms that ketoprofen molecules can affect the property and the inner structure of DPPC/DPPG monolayers during breathing. Furthermore, the results obtained using a mixed monolayer containing two major pulmonary surfactants DPPC/DPPG and ketoprofen molecules will be helpful for the in-depth understanding of the mechanism of inhaled administration therapy.