Abstract: Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation, which can lead to systemic inflammatory response syndrome (SIRS) and acute lung injury (ALI). Clinical evidence shows that platelet-transfusion after ECC can reduce the risk of lung injury, but the underlying mechanisms are still unknown. We recently established a mouse-ECC model that can effectively mimic many features of ECC-induced SIRS and ALI. Using this model, we tested the hypothesis that platelets play a considerable role in alleviating inflammatory responses in both the blood and lungs, thereby reducing the occurrence of ECC-related ALI. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to direct blood flow through a 1/32-inch external tube. All animals subjected to ECC (the ECC group and the platelet-transfusion-ECC (PLTs-ECC) group; each n = 10) survived 30 min of ECC and the sequent 60 min of observation. The mice in the PLTs-ECC group were given 0.1 mL of platelet-rich-plasma (PRP) at 25 min after the start of ECC. Blood analysis after ECC showed significant decreases in the levels of tumor necrosis factor-alpha, interleukin-6 and neutrophils elastase in plasma and lung tissue. Additionally, PRP treatment protected lung function and led to a notable decrease in circulating lactate. Histopathology showed that ECC induced lung inflammation, as expected, including alveolar congestion, haemorrhage, neutrophil infiltration, and alveolar wall thickening. The abovementioned changes were less pronounced in the PLTs-ECC group. Double immunofluorescence staining of lung sections showed a “mixed” yellow fluorescence signal in platelets and vascular endothelial cells (VECs) that was speculated to be from the tight binding of activated platelets with VECs and sub-endothelial matrices. Our results showed that PRP treatment led to significant respiratory function protection and mitigated the inflammatory responses in both the blood and lungs. Based on those observations, we propose two potential platelet-pulmonary protection mechanisms: (1) platelets reduce the release of inflammatory cytokines in the lung to prevent an inflammatory response and (2) platelets tightly bind to the endothelium and sub-endothelial matrices via the association of glycoprotein IB/IX/V with von Willebrand factor to repair damaged VECs and secrete sphingosine-1-phosphate (S1P), which helps maintain the integrity and promote the growth of vessel walls to reduce exudation and the retention of neutrophils in the lungs.