In our previous study, a new compound, octadecanoic acid-3, 4-tetrahydrofuran diester, possessing potent acaricidal activity was obtained from neem oil. This study performed RNA-seq transcriptomics and iTRAQ proteomics to uncover the acaricidal mechanism of the compound against Sarcoptes scabiei var. cuniculi. The results of transcriptomics indicated that after treatment with octadecanoic acid-3, 4-tetrahydrofuran diester, genes related to "Energy metabolism" were significantly up-/down-regulated, including citrate cycle, oxidative phosphorylation pathway and fatty acid metabolism. Proteomics analysis showed accordant changes of proteins related to oxidative phosphorylation pathway. The target proteins of the compound were NADH dehydrogenase, Ubiquinol-cytochrome c reductase, Cytochrome c oxidase, ATP synthase, enolase and superoxide dismutase. In transcriptomics-proteomics correlation analysis, the concordance rate between protein abundances and their corresponding mRNAs was 57%, while others (43%) were discordant changes, suggesting divergent regulating effects of octadecanoic acid-3, 4-tetrahydrofuran diester. These results suggested that the acaricidal mechanism of octadecanoic acid-3, 4-tetrahydrofuran diester attributed to interference with energy metabolism, especially oxidative phosphorylation pathway.