Recently, there has been increasing attention toward inhaled nanoparticles (NPs) to develop in-halation therapies for diseases associated with the pulmonary system and investigate the toxic ef-fects of hazardous environmental particles on human lung health. Taking advantage of microfluidic technology for cell culture applications, lung-on-a-chip devices with great potential in replicating the lung air-blood barrier (ABB) have opened new research insights in preclinical pathology and therapeutic studies associated with aerosol NPs. Surprisingly, the air interface in such devices, which makes them tremendously unique among the other common liquid-based cellular mi-crosystems and enables exposure of cultivated cells to the drug/toxic aerosols, has been largely disregarded. Accordingly, there exists a significant research gap in the comprehensive under-standing of the NPs’ dynamics in the lung-on-a-chip devices, which is momentous to control the injection of aerosols to the target area and attain a desired physiochemical efficacy. To address this research gap, a numerical parametric study is presented to provide a deep insight into the dynamic behavior of the airborne NPs in a gas-liquid dual-channel lung-on-a-chip device with a porous membrane separating the channels. A finite element multi-physics model is developed to enable a particle tracing investigation simultaneously in both air and medium phases to replicate the in vivo conditions avoiding laborious and costly experimental trials. The results include the impact of fluid flow as well as geometrical properties on the distribution, deposition, and translocation of the NPs with diameters ranging from 10 nm to 900 nm in the lung-on-a-chip. The obtained results strongly suggest the aerosol injection of NPs instead of the aqueous solution for more efficient deposition on the substrate of the air channel and higher translocation to the media channel. The current study proposes to optimize the affecting parameters to control the injection and delivery of aerosol par-ticles into the lung-on-chip device depending on the objectives of biomedical investigations and provides optimized values for some specific cases. Therefore, this study can assist scientists and researchers in complementing their experimental investigation in future preclinical studies on pulmonary pathology associated with inhaled hazardous and toxic environmental particles, as well as therapeutic studies for developing inhalation drug delivery.