Ischemia-reperfusion injury (IRI) after lung transplantation mainly contributes to the development of primary graft dysfunction. The Sprouty-related EVH1-domain-containing (SPRED) protein family inhibits the mitogen activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway. Our study was aimed at examining the role of SPRED2 in IRI in mice that received orthotopic lung transplantation. Syngeneic mouse lung transplantation was performed in wild-type C57BL/6 J (WT) mice and Spred2 knockout (Spred2-/-) mice on the C57BL/6 J background from the WT donor. Four hours after reperfusion, blood gas analysis was performed, and lung grafts were sacrificed and analyzed. By using arterial oxygen tension measurements and histological evaluation using Lung Injury Score, we revealed more severe IRI in the grafts transplanted to Spred2 recipients, which manifested as exacerbated airway epithelial cell damage, interstitial edema with hemorrhage and neutrophil infiltration. Intragraft ERK1/2 activation and expression levels of proinflammatory cytokines and chemokines in Spred2 recipients were higher than those in WT recipients. SPRED2 plays an important role in protecting the lungs from IRI in lung transplantation recipients. We suggest that focused treatments suppressing the activity of the MAPK/ERK pathway in transplantation recipients could be the potential therapeutic option for the prevention of lung IRI.