Evaluation of nasal spray drug absorption has been challenging because deposited particles are consistently transported away by mucociliary clearance during diffusing through the mucus layer. This study developed a novel approach combining Computational Fluid Dynamics (CFD) techniques with a 1-D mucus diffusion model to better predict nasal spray drug absorption. This integrated CFD-diffusion approach comprised a preliminary simulation of nasal airflow, spray particle injection, followed by analysis of mucociliary clearance and drug solute diffusion through the mucus layer. The spray particle deposition distribution was validated experimentally and numerically, and the mucus velocity field was validated by comparing with previous studies. Total and regional drug absorption for solute radius in the range of 1 − 110nm were investigated. The total drug absorption contributed by the spray particle deposition was calculated. The absorption contribution from particles that deposited on the anterior region was found to increase significantly as the solute radius became larger (diffusion became slower). This was because the particles were consistently moved out of the anterior region, and the delayed absorption ensured more solute to be absorbed by the posterior regions covered with respiratory epithelium. Future improvements in the spray drug absorption model were discussed. The results of this study are aimed at working towards a CFD-based integrated model for evaluating nasal spray bioequivalence.