Crizotinib is a targeted therapy for metastatic non-small cell lung cancer (NSCLC) that is ALK- or ROS1-positive, as well as for conditions such as ALK-positive anaplastic large cell lymphoma and inflammatory myofibroblastic tumor. However, the associated toxicity poses a significant challenge to its use. To mitigate this issue, a novel dry powder inhalation formulation was developed using Crizotinib-loaded polyethylene glycol-based polymeric nanoparticles (NPs). These nanoparticles were created through a nanoprecipitation approach and improved employing central composite design. The capabilities of the formulation were assessed with Anderson Cascade Impactor, revealing a fine particle fraction of 56.2% and a mass median aerodynamic diameter of around 1.5 μm, indicating appropriate aerodynamic characteristics for inhalation. Key properties of the optimized nanoparticles included Encapsulation efficiency (82.3%, Zeta potential (-31.9 mV), Particle size (167 nm), Polydispersity index (0.462) and Release efficiency (60.6%) In vitro studies indicated that the polymeric nanoparticles exhibited greater anticancer activity compared to free Crizotinib. Additional characterization using techniques like XRD, DSC, FTIR, and SEM confirmed that the polymeric nanoparticle formulation has promising physicochemical properties, suggesting it could enhance local drug delivery and efficacy in lung cancer treatment while potentially reducing systemic toxicity.