Objective To investigate the effect of cardamonin on ventilation‑associated lung injury (VALI). Methods According to the random number table method, 32 healthy C57BL/6 mice, aged 8‒12 weeks, were divided into four groups (n=8): a control group (the Sham group), a mechanical ventilation group (the M group), a mechanical ventilation+cardamonin group (the MC group, which was administered by gavage with cardamonin at 80 mg/kg 30 min before mechanical ventilation) and a mechanical ventilation+cardamonin+ML385 group (the MCM group, which were intraperitoneally injected with ML385 at 30 mg·kg−1·d−1 seven days before mechanical ventilation and gavaged with cardamonin at 80 mg/kg 30 min before mechanical ventilation). Then, a tidal volume of 28 ml/kg was set and mechanical ventilation was conducted for 4 h to establish a VALI model of mice. After ventilation, bronchoalveolar lavage fluid (BALF) was collected. The protein concentrations of BALF were detected by bicinchoninic acid (BCA) assay. The concentrations of tumor necrosis factor‑α (TNF‑α) and interleukin‑6 (IL‑6) in BALF were detected by enzyme linked immunosorbent assay (ELISA). The histopathological changes in the lungs were observed by hematoxylin‑eosin (H‑E) staining to evaluate pulmonary damage. The protein levels of nuclear factor‑erythroid 2‑related factor 2 (Nrf2) and superoxide dismutase 2 (SOD2) in lung tissues were detected by Western blot. Results Compared with the Sham group, the M group, MC group, and MCM group showed increases in pulmonary injury score, the concentrations of BALF, IL‑6, and TNF‑α (P<0.05), and the protein levels of Nrf2 and SOD2 protein in lung tissues (P<0.05). Compared with the MC group, the M group and MCM group showed increases in pulmonary injury score, and the concentrations of BALF,IL‑6, and TNF‑α, and decreases in the protein levels of Nrf2 and SOD2 in lung tissues (P<0.05). No differences were detected in each indicators between the M group and the MCM group (P>0.05). Conclusions Pretreatment of cardamonin can inhibit VALI by elevating the levels of Nrf2 and SOD2 in lung tissue.