High Altitude Pulmonary Edema (HAPE) is a life-threatening, non-cardiogenic pulmonary disorder caused by hypobaric hypoxia at high altitudes, leading to pulmonary hypertension, endothelial dysfunction, oxidative stress, and fluid accumulation in the lungs. Despite available therapeutic interventions, effective site-specific drug delivery remains a significant challenge due to poor bioavailability and systemic side effects. Nanotechnology-based drug delivery systems, particularly zinc oxide (ZnO) nanoparticles, offer a promising approach to improve drug stability, controlled release, and targeted delivery. Owing to their biocompatibility, large surface area, and ease of surface functionalization, ZnO nanoparticles have gained considerable attention as potential nanocarriers for pulmonary therapeutics. The present study aimed to synthesize ZnO nanoparticles through a green approach using P. roxburghii (L.) Sarg. leaf extract and develop a ZnO-based nanocomposite loaded with the bioactive compound 2-Propanone, 1-hydroxy-3-(4-hydroxy-3-methoxyphenyl) as a potential targeted drug delivery system for HAPE. The nanoparticles were synthesized using the aqueous leaf extract as a natural reducing and stabilizing agent, followed by loading of the selected bioactive compound. The synthesized materials were characterized using UV–Visible spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), and Energy Dispersive X-ray Spectroscopy (EDX). The UV–Visible spectrum showed a characteristic absorption peak at 377 nm, confirming ZnO nanoparticle formation. FTIR analysis demonstrated the involvement of phytochemicals in nanoparticle synthesis and verified successful loading of the bioactive compound through changes in characteristic functional group vibrations. XRD confirmed the crystalline hexagonal wurtzite structure of ZnO nanoparticles, while SEM revealed irregularly shaped particles with an average size of 24.71 nm. EDX analysis confirmed zinc and oxygen as the predominant elemental constituents, indicating the successful synthesis of high-purity ZnO nanoparticles. Overall, the findings demonstrate the successful green synthesis and characterization of a ZnO nanocomposite with desirable physicochemical properties. This nanocomposite represents a promising platform for targeted drug delivery, providing a foundation for future biological and pharmacological studies to evaluate its therapeutic potential in the management of High-Altitude Pulmonary Edema.