Oroxylin A, a natural flavonoid isolated from the medicinal herb Scutellaria baicalensis Georgi, has been reported to have anti-inflammatory and antioxidant properties. However, the effect of oroxylin A on cigarette smoke (CS)-induced lung inflammation remains unclear. In this study, the ability of oroxylin A to protect against CS-induced lung inflammation was detected in vivo and in vitro. Oroxylin A was administered intraperitoneally to mice 2h prior CS exposure every day for five consecutive days. BEAS-2B bronchial epithelial cells and RAW264.7 cells were used to investigate the molecular mechanism of oroxylin A in vitro. In vivo, the results showed that oroxylin A dose-dependently attenuated CS-induced lung histopathologic changes, expression of cytokines TNF-α, IL-1β, and MCP-1, and levels of oxidative biomarkers 3-nitrotyrosine and 8-isoprostane. Meanwhile, oroxylin A up-regulated GSH level and glutathione reductase (GR) activity in lung tissues. In vitro, oroxylin A significantly up-regulated Nrf2 expression and total cellular glutathione level in cigarette smoke extract (CSE)-stimulated cells. In addition, oroxylin A promoted Nrf2 binding to antioxidant response element (ARE) and up-regulated ARE-regulated gene such as heme oxygenase-1 (HO-1), GPx, and GR in CSE-stimulated cells. Oroxylin A could protect both epithelial cells and macrophages from damage by cigarette smoke in vitro. Taken together, these data indicated that oroxylin A attenuated oxidative stress and lung inflammation induced by CS via activating Nrf2 signaling pathway. Oroxylin A may be a protective agent against CS-induced lung inflammation and chronic obstructive pulmonary disease.