This study was designed to evaluate the possible histological and physiological changes induced by naproxen (an NSAID) and cefpodoxime (a cephalosporin derivative) administration on lung function of male albino rats. The overall physiological results revealed a significant (P ≤ 0.05) increase in packed cell volume (PCV), total white blood cells (WBCs) count, and lymphocyte count in all treated groups compared to control groups. In contrast, the results demonstrated a significant decrease in platelet (PLT). There were no significant differences in hemoglobin levels or red blood cell counts. Histological examination showed definite pathological lesions including thickening of alveolar walls, vascular congestion and infiltration of inflammatory cells. At higher doses, this drug ruptured the alveolar walls, caused fibrous masses and narrowed the bronchi. In conclusion, chronic or high-dose exposure to these drugs provokes abnormal physiological and histological responses in the lung which should warn against their therapeutic use.