Acute lung injury (ALI) is a common critical illness caused by intrapulmonary or extrapulmonary factors, which is accompanied by extremely high morbidity and mortality. Its pathogenesis is extremely complex and difficult to treat. Src homology 2 domain-containing protein tyrosine phosphatase (Shp2), a key cellular signal transduction molecule, plays a pivotal role in the pathophysiological processes of diverse diseases. Notably, in the context of pathogen infection, Shp2 regulates the functionality of cellular immunity, lung epithelial cells, and vascular endothelial cells. This review article highlights the significant role of Shp2 in the onset and progression of ALI, emphasizing its regulation of inflammatory response, apoptosis, and oxidative stress. Shp2 could emerge as a novel therapeutic target for ALI, offering valuable insights for the development of innovative drug candidates to treat this debilitating condition.