Public health reports indicate that high PM2.5 concentration can impair the respiratory health of the residents, especially for those affected by asthma. Therefore, there is a need to determine the deposition mechanism and efficiencies for PM2.5 in asthmatic human airways. In this study, gas flow dynamics and deposition fractions (DFs) of PM2.5 in generations 10–11 of Weibel's lung model were investigated where the two-phase gas-solid flow behaviors in healthy and asthmatic airways were considered. The gas phase was modeled as a transient laminar and incompressible flow while the discrete phase model (DPM) was applied for the particle phase. Three different air flow rates under rest, light activity, and moderate exercise were considered. For the healthy airways, higher total mass DFs were observed during a moderate exercise as compared to rest and light activity conditions. Deposition fractions were higher in asthmatic airways compared to those of healthy ones, stemming from tapering in the airways as well as complex secondary flow fields, namely, Dean vortices, in the folds. Deposition was mainly due to inertial forces of particles, but a small amount of PM2.5 was deposited near the entrance of asthmatic tube, as a result of the secondary flow. The numerical results revealed that the Dean vortices was an important factor for particle deposition. With increased DF, asthmatic people have a higher total respiratory dose of PM2.5 for a given exposure compared to healthy individuals. Thus contributing to their increased susceptibility to adverse health effects caused by PM2.5.