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Background: Single-lung ventilation (SLV) associated acute lung injury is similar to ischemia reperfusion (IR) injury which is usually occurred during lung surgery. Olmesartan (Olm), a novel angiotensin receptor blocker (ARB), has been reported to ameliorate organ IR injury. Several recent studies have shown that lung microbiota may be involved in pulmonary diseases, but the effect of pulmonary microbiota in SLV-induced lung injury has not been reported. This study aims to determine the mechanism of how Olm attenuates SLV induced lung injury. Results: 24 Sprague Dawley (SD) rats were randomly divided into four groups: S (sham) group; AS (ARB + sham) group, in which the rats were given 7 days Olm treatment before the sham surgery; I (injury) group, in which the rats underwent SLV for 1 h (right lung ventilation and left lung collapsed) and double lungs ventilation for 3 h; and the AI (ARB + injury) group. Our data showed that 7 days Olm treatment before modeling markedly alleviated SLV-induced lung injury by suppressing inflammation and reactive oxygen species. Bronchoalveolar lavage fluid samples from the injured side were collected for 16S rRNA gene-based sequencing analysis. A total of 53 different bacteria at the genus and species levels were identified, among which Burkholderiaceae was more enriched in group I compared with group S, but significantly decreased in AI group after Olm treatment. Fecal samples were then collected for gut microbiota analysis using 16S rRNA gene-based sequencing analysis, which revealed no significant difference between the A and AS group. Furthermore, the injured lung samples were collected for metabolomics analysis using liquid chromatography-mass spectrometry analyses to explore differential metabolites among all groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was applied to analyze the correlation between differential metabolites and lung microbiota. A total of 38 pathways were identified according to differential metabolites and 275 relevant pathways were enriched via analyzing the microbial community, 24 pathways were both identified by analyzing either metabolites or microbiota, including pyrimidine metabolism, purine metabolism, aminoacyl-tRNA biosynthesis and ATP-binding cassette transporter. Conclusions: Besides classical blockage of the renin-angiotensin II system, Olm could also alleviate SLV-induced lung injury by rewiring the interaction between pulmonary microbiota and metabolites.