The protecting effects of 3,5,4'-tri-O-acetylresveratrol (AC-Res) on seawater inhalation-induced acute respiratory distress syndrome (ARDS) by interfering with the activation of thioredoxin-1 (Trx-1) pathway were evaluated. Seawater inhalation-induced ARDS was assessed by magnitude of pulmonary edema and lung inflammation. Oxidative stress was tested by T-SOD activity and MDA content in lungs and cells. Besides, Trx-1, nuclear factor erythroid 2-related factor 2 (Nrf2) and Txnip expression were measured to explore how seawater induced oxidative stress and the mechanism by which AC-Res attenuated seawater inhalation-induced ARDS. The results showed that seawater inhalation increased wet-to-dry (W/D) ratios of lung tissues, enhanced secretion of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and disturbed the oxidative distress balance probably through interfering the activity of Trx-1 pathway. While treatment of AC-Res in vivo and Res in vitro reduced W/D ratios of lung tissues, decreased cytokines in lungs and maintained the oxidative stress balance through Trx-1 pathway. In conclusion, AC-Res treatment attenuated seawater inhalation induced ARDS via Trx-1 pathway.