4-Hydroxyphenylacetic acid (4-HPA) is an active component of Chinese herb Aster tataricus which had been widely used in China for the treatment of pulmonary diseases. The aim of this study is to investigate the effect of 4-HPA on seawater aspiration-induced lung injury. Pulmonary inflammation and edema were assessed by enzyme-linked immunosorbent assay (ELISA), bronchoalveolar lavage fluid (BALF) white cell count, Evans blue dye analysis, wet to dry weight ratios, and histology study. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) siRNA and permeability assay were used to study the effect of 4-HPA on the production of inflammatory cytokines and monolayer permeability in vitro. The results showed that 4-HPA reduced seawater instillation-induced mortality in rats. In lung tissues, 4-HPA attenuated hypoxia, inflammation, vascular leak, and edema, and decreased HIF-1 alpha protein level. In primary rat alveolar epithelial cells (AEC), 4-HPA decreased hypertonicity-and hypoxia-induced HIF-1 alpha protein levels through inhibiting the activations of protein translational regulators and via promoting HIF-1 alpha protein degradation. In addition, 4-HPA lowered inflammatory cytokines levels through suppressing hypertonicity-and hypoxia-induced HIF-1 alpha in NR8383 macrophages. Moreover, 4-HPA decreased monolayer permeability through suppressing hypertonicity and hypoxia-induced HIF-1 alpha, which was mediated by inhibiting vascular endothelial growth factor (VEGF) in rat lung microvascular endothelial cell line (RLMVEC). In conclusion, 4-HPA attenuated inflammation and edema through suppressing hypertonic and hypoxic induction of HIF-1 alpha in seawater aspiration-induced lung injury in rats.