Background Lung ischemia–reperfusion injury (LIRI) is a cause of poor prognosis in several lung diseases and after lung transplantation. In LIRI, matrix metalloproteinases and pyroptosis indicators change in parallel, both of them involvement of inflammatory modulation, but it is unclear whether they are related to each other. Methods We analyzed the matrix metalloproteinases (MMPs) changes from RNA sequencing (RNA-Seq) data of human transplantation and rat ischemia–reperfusion lung tissues in the Group on Earth Observations (GEO) database. Then established the mouse LIRI model to validate the changes. Further, the severity of lung injury was measured after intervening the matrix metalloproteinases changes with their selective inhibitor during Lung ischemia–reperfusion. Meanwhile, lung, pyroptosis was assessed by assaying the activity of Caspase-1 and interleukin 1β (IL-1β) before and after intervening the matrix metalloproteinases changes. Results The RNA-Seq data revealed that matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9) mRNA expression was elevated both in human lung transplantation and rat lung ischemia–reperfusion tissues, consistent with the change in our mouse model. At the same time, the activity of Caspase-1 and IL-1β were increased after LIRI. While, the lung injury was attenuated for the use of MMP2 and MMP9 selective inhibitor SB-3CT. Likewise, lung pyroptosis alleviated when treatment the mice with SB-3CT in LIRI. Conclusion We conclude that MMP2 and MMP9 are involved in the process of LIRI, the mechanism of which is related to the promotion of lung pyroptosis.