Effective therapeutics are not available for acute lung injury (ALI) and acute respiratory distress syndrome. Modified Xiaoqinglong decoction (M-XQL) is reported to effectively treat pneumonia but the underlying mechanisms are unclear. In this study, the therapeutic effect and mechanism of M-XQL were examined using a lipopolysaccharide (LPS)-induced ALI mouse model. The effects of M-XQL on lung injury, inflammatory responses and cell apoptosis were analyzed. Additionally, high-throughput sequencing was performed to evaluate the therapeutic mechanism of M-XQL. Pre-treatment with M-XQL significantly and dose-dependently mitigated the pathological changes and upregulation of pulmonary, nitric oxide content and cell apoptosis and serum TNF-α contents in the LPS-induced ALI mouse model. RNA sequencing analysis revealed that the expression of several arachidonic acid metabolism-associated genes in the LPS+high-dose M-XQL group differed from that in the LPS group. In particular, the Cbr2, Cyp4f18 and Cyp2e1 levels were upregulated, whereas the Alox12, Ptges and Ptges2 levels were downregulated in the LPS+high-dose M-XQL group. These results suggest that M-XQL exerts therapeutic effects in ALI mice by regulating arachidonic acid metabolism and exerting anti-apoptotic and anti-inflammatory effects. Thus, M-XQL is a potential agent for the clinical treatment of ALI.This article is protected by copyright. All rights reserved.