Cyclodextrins (CDs) enhance the solubility of poorly water-soluble drugs like ibuprofen (IBU), making them promising carriers for pulmonary drug delivery. This route lowers the required dose, minimizing side effects, which could be beneficial in treating cystic fibrosis. In this study, a nano-spray-drying technique was applied to prepare CD/IBU complexes using sulfobutylether-β-cyclodextrin (SBECD) or (2-Hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin chloride (QABCD) as carriers as well as mannitol (MAN) and leucine (LEU) as aerosolization excipients. Various investigation techniques were utilized to examine and characterize the samples, including a Master Sizer particle size analyzer, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). We applied in vitro Andersen Cascade Impactor measurements and in silico simulation analysis to determine the sample's aerodynamic properties. We also performed in vitro dissolution and diffusion tests. Applying formulations with optimal aerodynamic properties, we achieved an improved ~50% fine particle fraction values based on the Andersen Cascade Impactor measurements. The in vitro dissolution and diffusion studies revealed rapid IBU release from the formulations; however, the QABCD-based sample exhibited reduced membrane diffusion compared to SBECD due to the formation of electrostatic interactions.