BACKGROUND Sepsis is among the major antecedents of lung injury characterized by mitochondrial dysfunction. The functional integrity of the cell is influenced by mitochondrial dynamics. The present investigation evaluated the protective effects of dexmedetomidine against lung injury and speculates on the possible mechanism underlying its effects on mitochondrial function. MATERIAL AND METHODS Lung injury was induced by cecal ligation and puncture (CLP) in mice treated with 0.1, 0.3, or 0.5 mg/kg intravenous dexmedetomidine after a 30-minute surgery. The effects of dexmedetomidine were determined by the oxygenation index and the wet/dry weight ratio of the lung. The expression of mitochondrial protein was assessed by western blot analyses and real-time polymerase chain reaction, to determine the effects of dexmedetomidine on mitochondrial dynamics. The histopathology of the lung tissue was determined by hematoxylin and eosin staining, and TUNEL-positive cells were counted in TUNEL assays. Activity of caspase-3, caspase-8, and caspase-9 enzymes were determined by colorimetric assay. RESULTS Treatment with dexmedetomidine significantly attenuated changes in the oxygenation index and the wet/dry weight ratio in mice with CLP-induced lung injury. There was a significant decrease in pro-inflammatory mediators and markers of oxidative stress in the lung tissue of the dexmedetomidine-treated group compared to the negative control group. Moreover, treatment with dexmedetomidine attenuated the altered gene expression caused by mitochondrial fusion and fission in the lung tissue of mice with CLP-induced lung injury. The number of TUNEL-positive cells was significantly reduced in the dexmedetomidine-treated group compared to the negative control group. Moreover, dexmedetomidine ameliorated the altered activity of caspase-3, caspase-8, and caspase-9 enzyme in the lung tissues of CLP-induced lung injure mice. CONCLUSIONS Dexmedetomidine protected mice against CLP-induced lung injury by attenuating changes in mitochondrial fusion and fission.