Growth hormone releasing hormone (GHRH) antagonists enhance endothelial barrier function and counteract the LPS-induced lung endothelial hyperpermeability, the cardinal feature of the acute respiratory distress syndrome (ARDS). The unfolded protein response (UPR) is a multifaceted molecular mechanism, strongly involved in tissue defense against injury. The current study introduces the induction of UPR by GHRH antagonists, since those peptides induced several UPR activation markers, including the inositol-requiring enzyme-1α (IRE1α), the protein kinase RNA-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). On the other hand, the GHRH agonist MR-409 exerted the opposite effects. Furthermore, GHRH antagonists counteracted the kifunensine (UPR suppressor)-induced lung endothelial barrier dysfunction. Our observations suggest that UPR mediates, at least in part, the protective effects of GHRH antagonists in the lung microvasculature. To the best of our knowledge; this is the first study to provide experimental evidence in support of the hypothesis that UPR induction is a novel mechanism by which GHRH antagonists oppose severe human disease, including ARDS.