Arrested alveolarization is the pathological hallmark of bronchopulmonary dysplasia (BPD), a complication of premature birth. Here, the impact of systemic application of hydrogen sulfide (H₂S) on post-natal alveolarization was assessed in a mouse BPD model. Exposure of newborn mice to 85% O₂ for 10 days reduced the total lung alveoli number by 56% and increased alveolar septal wall thickness by 29%, as assessed by state-of-the-art stereological analysis. Systemic application of H₂S using the slow-release H₂S donor GYY4137 for 10 days resulted in pronounced improvement in lung alveolarization in pups breathing 85% O₂, compared with vehicle-treated littermates. Although without impact on lung oxidative status, systemic H₂S blunted leukocyte infiltration into alveolar airspaces provoked by hyperoxia, and restored normal lung interleukin 10 levels that were otherwise depressed by 85% O₂. Treatment of primary mouse alveolar type II (ATII) cells with the rapid-release H₂S donor NaHS had no impact on cell viability; however, NaHS promoted ATII cell migration. While exposure of ATII cells to 85% O₂ caused dramatic changes in mRNA expression, exposure to either GYY4137 or NaHS had no impact on ATII cell mRNA expression, as assessed by microarray, suggesting that the effects observed were independent of changes in gene expression. The impact of NaHS on ATII cell migration was attenuated by glibenclamide, implicating ion channels; and was accompanied by activation of Akt, hinting at two possible mechanisms of H₂S action. These data support further investigation of H₂S as a candidate interventional strategy to limit the arrested alveolarization associated with BPD.