The previous studies reported the antioxidant and anti-inflammatory properties of Schisandrin A (Sch A). This study aimed to investigate the ability of Sch A to protect against lung oxidative stress induced by the combination of cigarette smoke extract and lipopolysaccharide (LPS) in an in vitro model of chronic obstructive pulmonary disease (COPD). The cell viability was determined by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Colorimetry was used to detect the changes in antioxidant markers. Quantitative real-time polymerase chain reaction (RT-PCR) was used to examine the mRNA levels of interleukin-8 (IL-8) and heme oxygenase-1 (HO-1). The levels of IL-8 and HO-1 in the supernatant were determined by enzyme-linked immunosorbent assay, and Western blot analysis was performed to measure the phosphorylation and protein expression levels of nuclear factor-κB. Sch A inhibited the excessive proliferation of pulmonary epithelial cells, decreased malondialdehyde content, and increased the expression levels of superoxide dismutase and glutathione after the combined treatment of cigarette smoke extract and LPS. Also, Sch A downregulated the expression of IL-8 and upregulated the expression of HO-1 mRNA in lung epithelial cells and cell supernatants, and resulted in the downregulation of the protein expression level of phosphorylated nuclear factor-κB. Sch A inhibited the oxidative stress of lung epithelial cells induced by the combination of cigarette smoke extract and LPS. Sch A may be a potential therapeutic medication for COPD. 2020 Journal of Thoracic Disease. All rights reserved.