Acute lung injury (ALI) accompanied by an inflammatory response is an important complication after drowning. Macrophage activation and polarization are implicated in the inflammatory process of lipopolysaccharide (LPS)-induced ALI (LPS-ALI), but little is known about drowning-induced ALI (drowning-ALI). SH3GLB1 is a member of the endophilin family and has been shown to be involved in mitochondrial morphological changes and autophagy. However, its role in ALI remains unclear. Here,we performed single-cell profiling of lung immune cells isolated from the lungs of drowning-ALI mouse models. We found that the regulation of macrophages in drowning-ALI was similar to that in LPS-ALI. Specifically, SH3GLB1 was highly expressed in macrophages of drowning-ALI mouse models and was related to inflammation. Furthermore, SH3GLB1 deletion ameliorated LPS-ALI or drowning-ALI. In contrast, the restoration of SH3GLB1 expression provoked LPS-ALI and drowning-ALI. Mechanistically, SH3GLB1 was shown to interact with Rab7 to contribute to mitophagy, which resulted in mitochondrial dysfunction. Overall, these findings indicated that SH3GLB1 is required for Rab7-mediated mitophagy in inflammation during ALI and could be a novel target for lung protection.