Endoplasmic reticulum (ER) stress, defined as accumulation of unfolded proteins in ER, has been vastly studied in inflammatory processes as one of crucial determinants of cellular response. Decursin, a natural product isolated from Angelica gigas, has been reported to have anti-inflammatory property. In this study, using both in vivo (OVA-inhaled mice) and in vitro (primary murine tracheal epithelial cells) experimental systems, the effects of decursin on OVA-induced airway inflammation and AHR were determined. Furthermore, we checked the levels of various ER stress markers. ER stress markers including glucose regulated protein78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), activating transcription factor (ATF)-6, and X-box binding protein-1 (XBP-1) were markedly elevated in OVA-treated mice. Interestingly, treatment with decursin significantly reduced the increase of these ER stress markers. In addition, administration of decursin substantially reduced the number of inflammatory cells, AHR, and the increased levels of TH2 cytokines, TNF-α, and IL-1β in the lung of OVA-inhaled mice. We also found that decursin significantly prevented nuclear translocation of NF-kB p65 in lung tissues of OVA-treated mice. Moreover, administration of 4-phenyl butyric acid (4-PBA) which is one of potent ER stress inhibitors substantially inhibited OVA-induced asthmatic features as well as ER stress. These results indicate that decursin may attenuate antigen-induced airway inflammation and hyper-responsiveness, at least in part, through the modulation of ER stress.