Acrolein (Ac) is the second most commonly inhaled toxin, produced in smoke of fires, tobacco smoke, overheated oils, and fried foods; and usually associated with lung toxicity. Crocin (Cr) is a natural carotenoid with a direct antioxidant capacity. Yet, oral administration of crocin as a natural route is doubtful, because of poor absorbability. Therefore, the current study aimed to compare the potential protective effect of oral versus intraperitoneal (ip) crocin in mitigating Ac-induced lung toxicity. 50 Adult rats were randomly divided into 5 equal groups; Control (oral-saline and ip-saline) group, Cr (oral-Cr and ip-Cr) group, Ac group, oral-Cr/Ac group, and ip-Cr/Ac group; for biochemical, histopathological, and immunohistochemical investigations. Results indicated increased oxidative stress and inflammatory biomarkers in lungs of Ac-treated group. Histopathological and immunohistochemical examinations revealed lung edema, infiltration, fibrosis, and altered expression of apoptotic and anti-apoptotic markers. Compared to oral-Cr/Ac group, the ip-Cr/Ac group demonstrated remarkable improvement in the oxidative, inflammatory, and apoptotic biomarkers, as well as the histopathological alterations. In conclusion, intraperitoneal crocin exerts a more protective effect on acrolein-induced lung toxicity than the orally administered crocin.