Afatinib (AFA) is a potent aniline-quinazoline derivative, approved by the Food and Drug Administration (FDA) in 2013, as a first-line treatment for metastatic non-small cell lung cancer (NSCLC). However, its clinical application is highly limited by its poor solubility, and consequently low bioavailability. We hypothesize that loading of AFA into biodegradable PLGA nanoparticles for localized inhalational drug delivery will be instrumental in improving therapeutic outcomes in NSCLC patients. Formulated AFA nanoparticles (AFA-NP) were evaluated for physicochemical properties (particle size: 180.2 ± 15.6 nm, zeta potential: - 23.1 ± 0.2 mV, % entrapment efficiency: 34.4 ± 2.3%), formulation stability, in-vitro aerosol deposition behavior, and anticancer efficacy. Stability studies revealed the physicochemical stability of AFA-NP. Moreover, AFA-NP exhibited excellent inhalable properties (mass median aerodynamic diameter (MMAD): 4.7 ± 0.1 μm; fine particle fraction (FPF): 77.8 ± 4.3%), indicating efficient particle deposition in deep lung regions. With respect to in-vitro drug release, AFA-NP showed sustained drug release with cumulative release of 56.8 ± 6.4% after 48 h. Cytotoxic studies revealed that encapsulation of AFA into PLGA nanoparticles significantly enhanced its cytotoxic potential in KRAS-mutated NSCLC cell lines (A549, H460). Cellular uptake studies revealed enhanced internalization of coumarin-loaded nanoparticles compared to plain coumarin in A549. In addition, 3D tumor spheroid studies demonstrated superior efficacy of AFA-NP in tumor penetration and growth inhibition. To conclude, we have established in-vitro efficacy of afatinib-loaded PLGA nanoparticles as inhalable NSCLC therapy, which will be of great significance when designing preclinical and clinical studies. Graphical abstract.