Hydrogen sulfide (H2S), a novel signaling gasotransmitter in the respiratory system, may have anti-inflammatory properties in the lung. We examined the preventive and therapeutic effects of H2S on ozone-induced feature of lung inflammation and emphysema. C57/BL6 mice were exposed to ozone or filtered air over 6 weeks. Sodium hydrogen sulfide (NaHS), a H2S donor, was administered to the mice either before ozone exposure (preventive effect) or after completion of ozone exposure for 6 weeks (therapeutic effect). The ozone-exposed mice developed emphysema measured by micro-computed tomography and histology, airflow limitation measured by the forced maneuver system, and increased lung inflammation with augmented IL-1β, IL-18 and MMP-9 gene expression. Ozone-induced changes were associated with increased NLRP3-caspase-1 activation and p38 MAPK phosphorylation and decreased Akt phosphorylation. NaHS both prevented and reversed lung inflammation and emphysematous changes in alveolar space. In contrast, NaHS prevented but did not reverse ozone-induced airflow limitation and bronchial structural remodeling. In conclusion, NaHS administration prevented and partially reversed ozone-induced feature of lung inflammation and emphysema via regulation of the NLRP3-caspase-1, p38 MAPK and Akt pathways.