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Lung microvascular endothelial cell (EC) dysfunction is the pathological hallmark of acute respiratory distress syndrome. Heat shock protein 90 (HSP90) is a key regulator in control of endothelial barrier disruption and inflammation. Our recent study has demonstrated that ubiquitin-specific peptidase 40 (USP40) preserves endothelial integrity by targeting HSP90β for its deubiquitination and inactivation. Indole-3-acetic acid (IAA), a plant hormone of the auxin class, can also be catabolized from dietary tryptophan by the intestinal microbiota. Accumulating evidence suggests that IAA reduces oxidative stress and inflammation and promotes intestinal barrier function. However, little is known about the role of IAA in endothelial cells and acute lung injury. In this study, we investigated the role of IAA in lung endothelial cell function in the context of acute lung injury. IAA exhibited EC barrier protection against LPS-induced reduction in transendothelial electrical resistance and inflammatory responses. The underlying mechanism of IAA on EC protective effects was investigated by examining the influence of IAA on degrees of HSP90 ubiquitination and USP40 activity. We identified that IAA, acting as a potential activator of USP40, reduces HSP90 ubiquitination, thereby protecting against LPS-induced inflammation in human lung microvascular endothelial cells as well as alleviating experimental lung injury. Furthermore, the EC protective effects of IAA against LPS-induced EC dysfunction and lung injury were abolished in USP40-deficient human lung microvascular endothelial cell and lungs of USP40 EC-specific knockout (USP40 cdh5-ECKO ) mice. Taken together, this study reveals that IAA protects against LPS-induced EC dysfunction and lung injury through the activation of USP40.