Background Ventilator-induced lung injury (VILI) is the most common complication in the mechanical ventilation in clinic. The pathogenesis of VILI has not been well understood. The SRY related High Mobility Group box group-F family member 11(Sox11) is a protein associated with lung development. The focal adhesion kinase(FAK) is a cytoplasmic tyrosine kinase and is regulated by Sox11. The present study, therefore, was undertaken to explore the potential role of Sox11 and FAK in VILI. Methods High volume mechanical ventilation(HMV) was used to establish mouse VILI model under anesthesia. The lung injury was evaluated by analyzing the lung weight, bronchoalveolar lavage fluid, histopathological changes and apoptosis of the lung. The Sox11 and FAK expressions in the lung were investigated by real-time qPCR, western blot and immunohistochemistry analysis. Results HMV induced VILI simultaneously companied with decreased expressions of Sox11 and FAK in alveolar epithelial and interstitial cells either in gene and protein levels. Transfection of Sox11 plasmid significantly upregulated expressions of Sox11 and FAK in gene and protein levels in the lung and particularly effectively alleviated VILI. Furthermore, FAK antagonism by PF562271(FAK antagonist) blocked the alleviating effect of Sox11 plasmid transfection on the VILI. Conclusion The dysregulation in the Sox11 and FAK after HMV play an important role in the pathogenesis of VILI, and facilitating the activity of Sox11 and FAK might be an effective target and potential option in the prevention and treatment of VILI in clinic. (C) 2019 The Authors. Published by Elsevier Inc.