Purpose: To investigate the anti-inflammatory mechanism of dexmedetomidine (Dex), an α2-adrenoceptor (α2-AR) agonist, on renal ischemia-reperfusion (RIR)-induced acute lung injury (ALI). Methods: RIR was performed in C57BL/6J mice by bilateral renal pedicles occlusion for 60min and reperfusion for 24h. Mice were pre-treated with or without Dex alone or combined atipamezole (Atip), an α2-AR antagonist. The pulmonary histopathological evaluation, arterial blood gas analysis, cell count and multiple cytokines examination in BALF, global inflammation status assessment in lung tissue and alveolar macrophages phenotype investigation were accomplished. In vitro, the polarity of mice alveolar macrophages (MH-S) treated with serum from normal or RIR mice were indirectly detected by qPCR. Results: The results indicated that, compared to RIR animal, dexmedetomidine reduced lung injury and significantly promoted macrophage polarization towards an anti-inflammatory M2 phenotype in the pulmonary tissue. Meanwhile, the reduction of inflammatory cell infiltration and pro-inflammatory cytokines levels were observed. In vitro studies confirmed that dexmedetomidine skewed MH-S towards M2 phenotype after stimulation of RIR serum. After administration of the atipamezole, these above effects were abolished. Conclusion: Dexmedetomidine ameliorates renal ischemia-reperfusion induced ALI through activation of α2-adrenoceptor to skew macrophages towards an anti-inflammatory phenotype to reduce pulmonary global inflammation.