Inhalational lung injury often leads to morbidity and mortality during fire disasters. In this study, we aimed to evaluate the protective effects of edaravone combined with dexamethasone on smoke-induced inhalational lung injury. Sprague-Dawley rats were divided into five groups, namely, the control, model (inhalation), and three treatment groups (edaravone, dexamethasone, and edaravone combined with dexamethasone). After drug intervention in the acute lung injury model, arterial blood gas, wet:dry weight ratio of the lung tissue, bronchoalveolar lavage fluid, and pulmonary histopathology were determined. The production of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), inflammatory cytokines, peroxidase and apoptosis were further analyzed to explore the underlying mechanisms. The results of blood gas and inflammatory cytokine analysis and the histopathological data demonstrated that edaravone combined with dexamethasone had obvious protective effects on smoke infiltration and tissue injury. Moreover, after the co-administration of edaravone and dexamethasone, malondialdehyde and myeloperoxidase levels in the lung tissue decreased, whereas those of glutathione peroxidase and superoxide dismutase were elevated. In addition, this drug combination could inhibit smoke-induced apoptosis in lung tissues by reducing the cleavage of caspase-3, caspase-9, and poly ADP-ribose polymerase (PARP), and also reverse smoke-mediated mitochondrial dysfunction, including ROS generation, loss of MMP, early release of cytochrome C, second mitochondrial activator of caspases, and apoptosis-inducing factor. In conclusion, edaravone combined with dexamethasone had a protective effect on smoke-induced inhalational lung injury in rats and can be further explored as an attractive therapeutic option for the treatment of smoke inhalation-induced pulmonary dysfunction.