Allergic bronchopulmonary aspergillosis (ABPA) results from hypersensitivity to Aspergillus fumigatus colonizing the airway mucus layer and lung cavity. Although itraconazole (ITZ) is a first-line antifungal agent, systemic administration may cause adverse effects and limited drug exposure at pulmonary infection sites. Dry powder inhalers (DPI) enable direct pulmonary delivery, but inhaled particles must overcome barriers such as mucus entrapment, macrophage phagocytosis, and limited drug dissolution in lung fluid. Nanoparticle-in-microparticle (NIM) formulations address these challenges by enabling inhalable microparticles to deposit in the lung and release nanoparticles capable of diffusing through mucus and avoiding macrophage uptake. In this study, an ITZ-loaded NIM DPI formulation was developed to improve pulmonary delivery and antifungal efficacy for ABPA treatment. ITZ nanoparticles were prepared by ball-milling using polyvinyl alcohol and sodium lauryl sulfate and spray-dried to produce inhalable NIM particles. Redispersibility, mucus permeability, and macrophage uptake were evaluated to assess pulmonary barrier penetration, followed by in vivo pharmacokinetic and pharmacodynamic studies. The NIM particles showed suitable aerodynamic size for pulmonary delivery (Dv50: 1–5 μm) and rapidly disintegrated into nanoparticles in simulated lung fluid. The released nanoparticles exhibited enhanced diffusion through artificial mucus and minimal macrophage uptake. In vivo studies demonstrated higher ITZ concentrations in lung tissue and bronchoalveolar lavage fluid than oral administration and significantly reduced fungal burden, indicated by decreased colony forming units and galactomannan levels. These results indicate that the ITZ-NIM DPI formulation improves pulmonary drug retention and antifungal efficacy for ABPA treatment