Hydrogen sulfide (H2S) is a popular toxic environmental gas and industrial pollutant, which can be harmful to multiple organ systems of both human and livestock, especially to the respiratory system. However, the injury mechanism of H2S exposure to lung remains poorly understood. In this study, pig lung was selected as a H2S exposure model for the first time. We first examined the histological damage and the mRNA expression of pro-inflammatory genes of lung in pigs exposed to H2S. Histopathology change and increased mRNA level of pro-inflammatory cytokines demonstrated that H2S exposure indeed induced inflammatory injury in the porcine lung. We then performed TMT-based quantitative proteomics analysis to probe the injury molecular mechanism. The proteomics results showed that 526 proteins have significant changes in abundance between control and H2S treated swine. Further validation analysis of some H2S responsive proteins using both Real-time quantitative PCR and western blotting demonstrated that proteomics data are reliable. KEGG pathway analysis revealed that these proteins were involved in antigen processing and presentation, complement and coagulation cascade, IL-17 signaling pathway, ferroptosis and necroptosis. Our data suggest that H2S exposure induced immune suppression, inflammatory response and cell death. These findings provide a new insight into the complexity mechanisms of H2S induced lung injury, and offer therapeutic potential as drug targets with a view towards curing the intoxication caused by H2S.