<jats:p>Pulmonary fibrosis (PF) is a life-threatening interstitial lung disease. In this study, we tried to reveal the model of action between high-mobility group box 1 (HMGB1) and <jats:italic>α</jats:italic>-smooth muscle actin (<jats:italic>α</jats:italic>-SMA) and the protective role of gefitinib in pulmonary fibrosis induced by the administration of bleomycin aerosol in mice. For the mechanism study, lung tissues were harvested two weeks after modeling to detect the coexpression of HMGB1 and <jats:italic>α</jats:italic>-SMA by immunohistochemistry and immunofluorescence staining. Protein-DNA interactions were analyzed using a pulldown assay to study the relationship between HMGB1 and <jats:italic>α</jats:italic>-SMA. For the gefitinib treatment study, the mice were divided into three groups: phosphate-buffered saline (PBS) control group, PBS-treated PF group, and gefitinib-treated PF group. Gavage of gefitinib or PBS (20 mg/kg/day) was performed after bleomycin treatment for two weeks until the mice were sacrificed. Lung and blood samples were collected to assess the histological changes, oxidative stress, and expression of NOXs, HMGB1, EGFR, MAPKs, AP-1, and NF-<jats:italic>κ</jats:italic>B to determine the curative effect and related molecular mechanisms. The results revealed the high coexpression of <jats:italic>α</jats:italic>-SMA and HMGB1 in some interstitial cells in the fibrotic lung. The DNA-protein pulldown analysis proved that HMGB34367 acted as a novel transcriptional factor for the <jats:italic>α</jats:italic>-SMA promoter and participated in the eventual development of pulmonary fibrosis. Second, gefitinib could significantly decrease lung fibrotic changes and the level of MDA and recover the T-AOC level. Meanwhile, gefitinib could also reduce the NOX1/2/4, HMGB1, p-EGFR, p-ERK, p-JNK, p-P38, p-NF-<jats:italic>κ</jats:italic>B, p-c-Jun, and p-c-Fos expression levels in fibrotic lungs. The present study suggested that gefitinib could alleviate lung fibrosis through the HMGB1/NOXs-ROS/EGFR-MAPKs-AP-1/NF-<jats:italic>κ</jats:italic>B signal in bleomycin-induced pulmonary fibrosis.</jats:p>