Endothelial-inflammatory cell crosstalk regulates tissue injury in sepsis. We hypothesized that liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, would attenuate murine sepsis-induced acute lung injury (ALI) and have specific endothelial protective effects using a two-hit model of ALI. Sepsis was induced by intraperitoneal injection of cecal slurry (CS) or 5% dextrose (control) followed by hyperoxia (HO;FiO₂=0.95) or room air (control, FiO₂=0.21). Mice were pre-treated twice daily with injections of liraglutide (0.1mg/kg) or saline for 3-days prior to CS+HO. At 24-hours post-CO+HO, we analyzed weight loss, severity of illness, and survival and collected bronchoalveolar lavage (BAL) fluid and lung tissue. We measured BAL inflammatory cells, cytokine and protein concentration, epithelial injury markers (receptor for advanced glycation end products) and lung tissue cytokine expression, wet-to-dry weight ratios and histologic injury. To test the direct endothelial effects, we cultured primary human lung microvascular endothelial cells (HLMVECs), treated with LPS+/- liraglutide, and measured barrier dysfunction by Electric Cell Impedance Sensing (ECIS) and xPert assay. Compared to saline treatment, liraglutide improved sepsis-induced severity of illness and mortality, reduced BAL inflammatory cells (49.5 [IQR 45.8, 54.8] v 10.5 [IQR 6, 22.5] x 10⁴ cells; p=0.002) and attenuated alveolar-capillary barrier dysfunction, epithelial injury, and histologic injury. Liraglutide pretreatment of HLMVEC's attenuated LPS mediated barrier dysfunction (ECIS and xPert). GLP-1R agonists have the potential to attenuate ALI via direct effects on endothelial-inflammatory cell crosstalk.