ObjectiveSmoke inhalation lung injury (SILI) is a common complication in fires and wars, characterized by acute onset and severe condition. Pirfenidone (PFD), a new small‐molecule drug, has been shown to improve lung function and inhibit pulmonary fibrosis and inflammation. This study aimed to elucidate the effect and underlying mechanism of PFD on SILI in rats.Materials and MethodsSILI rats were constructed using a homemade smoking device, which was then treated with PFD. The blood was collected from the abdominal aorta, and the arterial blood gas was detected. The productions of oxidative stress markers and inflammatory cytokines in plasma were measured by enzyme linked immunosorbent assay assay. Moreover, the alveolar surface area, wet:dry weight ratio of the lung tissues, and bronchoalveolar lavage fluid (BALF) were determined as well. The pulmonary histopathology, cell apoptosis, and the related proteins of nuclear factor kappa B (NF‐κB) pathway were determined by hematoxylin‐eosin staining, TdT‐mediated dUTP‐biotin nick end labeling, and western blot assays, respectively.ResultsPFD had a significant protective effect on SILI via inhibiting oxidative stress, inflammation, and apoptosis. Mechanistically, PFD inhibited the activation of NF‐κB pathway in vivo. Moreover, activation of NF‐κB pathway attenuated the PFD‐mediated protective effect against SILI.ConclusionsThese data demonstrate that PFD alleviates SILI of rats via the NF‐κB signaling pathway, which provides an attractive therapeutic option for SILI treatment.