The present study aimed to synthesize tiotropium bromide (TIO)-loaded generation 5 polyamidoamine dendrimers (TIOPAMAM-G5-DMs) using a solvent-free microwave assisted synthesis (MAS) for the treatment of pulmonary acidosis, a condition associated with decreased blood pH due to bronchoconstriction. The encapsulation of TIO into PAMAM-G5-DMs was achieved using MAS Michael addition and amidation reactions, following green chemistry principles. The DMs demonstrated particle size of 460.68 ± 1.38 nm, entrapment efficiency of 92.4 ± 0.44%, controlled release profiles of 90.4 ± 0.62% and 76 ± 0.84% in media of pH 6.8 and 7.4, respectively, and high buffering capacity (25 mL/pH units) using a proton sponge effect for the release of the drug into the system as compared to the conventional formulation. A synergistic rat model was used to compare the pharmacokinetics (PK) of marketed and DM-based formulations. The results showed a mean C_max of 1987 ng/mL, t_max of 6 h, AUC of 10013863.5 ng.h/mL, and t½ of 18.59 h, respectively. The DMs exhibited low cytotoxicity, good biocompatibility, and higher IC₅₀ value (> 10 μg) on human lung epithelial cell line BEAS-2B. Thus, our study introduces a cutting-edge alternative approach for treating pulmonary acidosis using PAMAM-DMs with proton sponge effect.