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Genus Quercus is a well-known source for its polyphenolic content and important biological activity. Plants belonging to the Quercus genus were traditionally used in asthma, inflammatory diseases, wound healing, acute diarrhea, and hemorrhoid. Our work intended to study the polyphenolic profile of the Q. coccinea (QC) leaves and to assess the protective activity of its 80% aqueous methanol extract (AME) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Together, the potential molecular mechanism was investigated. Nineteen polyphenolic compounds (1-18), including tannins, flavone, and flavonol glycosides. Phenolic acids and aglycones were purified and identified from the AME of QC leaves. Treatment with AME of QC showed an anti-inflammatory effect evidenced by a remarkable decline in the count of white blood cells and neutrophils which was in harmony with decreasing the levels of high mobility group box-1, nuclear factor kappa B, tumor necrosis factor-α, and interleukin 1 beta. In addition, the antioxidant activity of QC was documented through the significant reduction in malondialdehyde level and elevation of reduced glutathione level and superoxide dismutase activity. Furthermore, the mechanism involved in the pulmonary protective effect of QC involved the downregulation of the TLR4/MyD88 pathway. The AME of QC showed a protective effect against LPS-induced ALI through the powerful anti-inflammatory and antioxidant activities which are linked to its abundancy with polyphenols., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)