Petroleum products-petrol, kerosene, and diesel-composed of volatile organic constituents contribute to air pollution. Exposure of gas station attendants (GSAs) to petroleum products fumes (PPFs) may account for occupation-related predisposition to respiratory toxicity and disease pathogenesis. We simulated GSA exposure to PPF inhalation and examined their effect on oxido-inflammatory responses, toxicity, and histopathological alterations in rat lungs, following 8-hours daily exposure for 60 and 90 days. Reactive oxygen and nitrogen species (RONS), oxidative stress and inflammatory biomarkers, namely: superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST), TNF-α, IL-1β, xanthine oxidase (XO), nitric oxide (NO) activity were evaluated. Besides, histopathological examination of the lungs and trachea of exposed rats, PPF exposure resulted in significant (P < .05) increases in RONS, biomarkers of oxidative stress, pro-inflammation cytokines, and reduced (P < .05) GSH levels in rats, secondary to histopathological alteration in lungs and trachea cytoarchitecture examined in an exposure-durationdependent manner. We conclude, therefore, that the observed biochemical and histological changes create a microenvironment that is permissive to diseases pathogenesis of the respiratory system via oxido-inflammatory mechanistic pathways.