Tadalafil (a phosphodiesterase-5 inhibitor) is a choice for treatment of pulmonary arterial hypertension (PAH) that is known as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest and ≥30 mmHg during exercise with reduced cardiac output. The aim of this study was to prepare inhalable tadalafil nanocomposites as a dry powder formulation by spray drying technique for increasing bioavailability and treatment efficacy, as well as decreasing systemic side effects. The D-optimal design was used for optimization of formulation parameters. Microparticle size, morphology, crystallinity, density, solubility, redispersion (%), and in-vitro inhalation performance of tadalafil nanocomposites were investigated as physicochemical characteristics. Pharmacokinetic parameters were also evaluated in plasma and lung tissue of Wistar rats after intratracheal insufflation and compared with a control group receiving an oral tadalafil marketed product (dose = 10 mg/kg). The suggested optimum formulation contained stable amorphous particles with almost rounded shape and corrugated surface that were completely redispersed in the lung simulated medium with the mass median geometric diameter of 3.2 μm, density of 1.4 g/cm³, fine particle fraction based on emitted dose (%) of 57.2 ± 6.5%, and 13.7-fold enhancement in dissolution rate. In-vivo studies showed that the ratio of AUC_{0-24h lung}/AUC_{0-24h plasma}, achieved in the treated group after intratracheal insufflation, was significantly higher than the control group that means high local drug concentration and more efficacy. Besides, plasma data analysis indicated high value of MRT (2.3-fold) and t_max (3.7-fold) after intratracheal insufflation of tadalafil nanocomposites in comparison with the conventional oral route, indicating longer retention of tadalafil molecules in the lungs and their slower entry to the systemic blood circulation. In conclusion, it seems that inhalable tadalafil nanocomposites can be introduced as an alternative to oral tadalafil in the treatment of PAH.