In an effort to treat preterm neonates who are already suffering or are at high risk for chronic pulmonary illness, the comprehensive investigation has recently been focused on the intratracheal administration of corticosteroid drugs employing an innate lung surfactant as a drug carrier. A novel approach to utilize exogenous surfactant preparation as a drug delivery vehicle for corticosteroids, which are the inflammation-reducing agents for lung diseases has not been comprehensively investigated. The direct corticosteroid drugs administered through pulmonary surfactants would impair their surface activity and exacerbate normal breathing cycles. This study was conducted to characterize the physiological interaction between frequently used inhaled corticosteroid, mometasone furoate, and relevant composition of lung surfactants by using the in vitro and in silico methods. The major objective of this work is to elucidate the effects of glucocorticoids on the structural and dynamical characteristics of the lung surfactant as well as the effects of the drug on the ability of the surfactant monolayer to reduce surface tension during mechanical breathing. Our results from the Langmuir experiment and atomic force microscopy imply that mometasone furoate concentrations less than 4.18% w/w might not strongly influence the physicochemical characteristics of the surfactant molecules representing the feasible concentration for pulmonary drug delivery. Beyond this range, mometasone furoate concentrations cause intensified film fluidization that leads the surfactant film to collapse at lower surface pressure, which is also verified by the in silico study. The failure of the drug to permeate into the lipid bilayer is most likely what causes this collapse. On the other hand, for inhalation breathing, the monolayer forms pores induced by the high drug concentrations. Our investigation also reveals that mometasone furoate exhibits different spreading behaviors because of their affinities to the surfactant molecules. This work may have implications for the use of inhaled steroids in the treatment of asthma in addition to its translational significance in the management of chronic lung disease.