Recently published studies have proposed that amorphous drug nanoparticles in gastrointestinal fluids may be beneficial for the absorption of poorly soluble compounds. Nanosized drug particles are known to provide rapid dissolution rates and, in some instances, a slight increase in solubility. However, in recent studies the differences observed in vivo could not be explained solely by these attributes. Given the high dose and very low aqueous solubility of the study compounds, rapid equilibration to the drug saturated solubility in gastrointestinal fluid would occur independent of the presence of nanoparticles. Alternatively, it has been proposed that drug nanoparticles (ca. ≤200 to 300 nm) may provide a “shuttle” for drug across the unstirred water layer (UWL) adjacent to the intestinal epithelium, particularly for low solubility/lipophilic compounds where absorption may be largely UWL-limited. This transport mechanism would result in a higher unbound drug concentration at the surface of the epithelium for absorption. This study evaluates this mechanism using a simple modification of the effective permeability to account for the effect of drug nanoparticles diffusing across the UWL. The modification can be made using inputs for solubility and nanoparticle size. The permeability modification was evaluated using three published case studies for amorphous formulations of itraconazole, anacetrapib, and enzalutamide, where the formation of amorphous drug nanoparticles upon dissolution resulted in improved drug absorption. Absorption modeling was performed using GastroPlus™ to assess the impact of the nano-modified permeability method on the accuracy of model prediction compared to in vivo data. Simulation results were compared to those for baseline simulations using an unmodified effective permeability. The results show good agreement using the nano-modified permeability, which described the data better than the standard baseline predictions. The nano-modified permeability method can be a suitable, fit-for-purpose in silico approach for evaluating or predicting oral absorption of poorly soluble, UWL-limited drugs from formulations that produce a significant number of amorphous drug nanoparticles.