A physiologically based pharmacokinetic model was developed for accurately characterizing and predicting the in vivo fate of long-circulating inorganic nanoparticles (NPs). This model is built based on direct visualization of NP disposition details at the organ and cellular level. It was validated with multiple data sets, indicating robust inter-route and interspecies predictive capability. We suggest that the biodistribution of long-circulating inorganic NPs is determined by the uptake and release of NPs by phagocytic cells in target organs.