Objective To investigate the effect of dexmedetomidine（DEX） on lung injury in mice by regulating Toll-like receptor-4 （TLR4）/aconitate decarboxylase 1（ACOD1） immune metabolism coupling in macrophages. Methods RAW264.7 cells were divided into control group，LPS group，and LPS+DEX group，and Western blot and ELISA were used to measure the expression levels of TLR4，ACOD1，and proinflammatory cytokines. C57 BL/6 mice were divided into control group，cecal ligation and puncture（CLP） group，and CLP+DEX group，and experiments were conducted to observe the 7-day survival rate and lung injury of mice，as well as the expression levels of TLR4 and ACOD1 in lung tissue and the expression levels of proinflammatory cytokines in alveolar macrophages and peripheral blood. Subsequently，Acod1 systemic knockout（Acod1^-/- ） mice were used to observe the condition of lung injury after CLP+DEX treatment and the changes after CLP+DEX treatment in wild-type（WT） mice. Finally，bone marrow-derived macrophages（BMDMs） were extracted from WT and Acod1^-/- mice to measure the expression level of inducible nitric oxide synthase（iNOS） in macrophages. Results After LPS stimulation of RAW264.7 cells，there were increases in the expression levels of TLR4，iNOS，tumor necrosis factor-α（TNF-α），and interleukin-6（IL-6），which were reduced after DEX treatment. In vivo experiments showed that DEX treatment reduced the 7-day mortality rate，diffuse alveolar injury，pulmonary edema，and the expression levels of the proinflammatory cytokines TNF-α and IL-6 in peripheral blood in mice with CLP-induced acute respiratory distress syndrome/acute lung injury，and it also reduced the expression level of iNOS in lung tissue and alveolar macrophages. In addition，DEX reduced the expression level of TLR4 in the lung tissue of CLP mice. Knockout of the Acod1 gene reversed the therapeutic effect of DEX，aggravated lung injury，and increased the expression of iNOS in BMDMs. Conclusion Dexmedetomidine can regulate TLR4/ACOD1 immune metabolism coupling in macrophages，reduce the release of inflammatory cytokines in macrophages after LPS stimulation，and alleviate acute lung injury in mice.