Background <p>Long-term recurrent exposure to petroleum fumes poses a substantial occupational risk, specifically among individuals in gasoline stations. They are routinely exposed to the inherent toxic constituents of petrol and diesel, such as hydrocarbons, VOCs, and trace elements, during their routine activities, including fuel dispensing, handling, storage, transport, and refining processes. Due to inadequate safety measures allow these toxicants into the lungs, cross the pulmonary barrier, enter the circulation and subsequently reach the brain through disrupting the lung-brain axis (LBA). The present study aims to investigate the sub-chronic effects of petrol and diesel fumes on respiratory and neurocognitive functions, along with therapeutic efficacy of saffron-derived bioactive constituent, crocin (10&#xa0;mg/kg, i.p.), as a potential neuroprotective agent.</p> Methods <p>The pulmonary dysfunctions were estimated by cytokine analysis in the broncho-alveolar lavage fluid (BALF), antioxidant activity, Evans blue dye (EBD) extravasation for microvascular airway leakage and histology analysis. Neurocognitive impairments were elucidated by behavioural paradigm, along with determination of acetylcholinesterase activity (AChE), antioxidant levels, protein biomarkers and EBD vascular permeability assay for blood-brain-barrier (BBB) permeability, neuronal count and histopathological examination.</p> Results <p>Intraperitoneal administration of crocin was found to attenuate anxiety-like behaviour and improve associative memory following intoxication with petroleum fumes. These effects are accompanied by enhanced antioxidant defence (SOD, GSH, CAT) and reduced lipid peroxidation in both lungs and brain tissues. Additionally, crocin downregulates the expression of amyloid precursor protein (APP) (<i>p</i> &lt; 0.05) in DE animals, thereby preserving capillary barrier integrity and BBB permeability. Histopathology results confirmed that crocin can prevent alveolar damage and inflammatory cell infiltration, while improve neuronal integrity and increasing neuronal density in the hippocampus.</p> Conclusion <p>These findings indicate partial protection of the pulmonary and neurological systems with crocin. However, no significant effects were observed on the spatial memory, cytokine levels and APP expression at the tested dose. Therefore, future studies are warranted to optimise the dosing regimen of crocin for preventing petroleum product-induced pulmonary and neurological complications.</p> Graphical abstract <p></p>