<p>Helium–oxygen mixtures (HeliOx) have been proposed to enhance aerosol drug delivery by reducing airflow turbulence and facilitating deeper penetration of medications into the respiratory tract. However, previous studies on HeliOx efficacy have yielded mixed results, often limited by unrealistic anatomical models and steady-state assumptions, and focus on restricted sections of the airway. This study aims to address these limitations by investigating the transport and deposition of pharmaceutical aerosols in HeliOx compared to atmospheric air using a realistic, computed tomography-based nose-to-lung respiratory tract model that extends from a face mask to the 13th generation of tracheobronchial airways. Experimentally measured, dynamic breathing profiles were incorporated to simulate realistic inhalation conditions. Pharmaceutical aerosols with diameters ranging from 1 to 100 µm were released under two conditions: ambient air and HeliOx. Computational fluid–particle dynamics simulations were performed to model and visualize the transport and deposition patterns of aerosols throughout the respiratory tract during inhalation. The simulation results indicate that HeliOx promotes more steady airflow with reduced turbulence, facilitating a deeper delivery of drug aerosols compared to ambient air. Specifically, HeliOx reduced turbulence intensity in the nasal cavity, larynx, and upper trachea regions, and enhanced aerosol penetration to the lower respiratory tract, increasing the deposition fraction in the deeper lung regions. These findings suggest that utilizing HeliOx as a carrier gas can improve deep lung-targeted drug delivery, potentially enhancing therapeutic outcomes for pulmonary diseases.</p>