Mitochondrial quality control is crucial in sepsis-induced acute lung injury (SI-ALI). Our study investigates how the intracellular protein TBC1D15 regulates mitochondrial quality to improve SI-ALI. We found TBC1D15 levels significantly decreased in the whole blood of sepsis patients, monocytes, lung tissue from SI-ALI mice, and the MLE-12 cellular model (mouse lung epithelial cells). Overexpression of TBC1D15 using adeno-associated viral and lentiviral vectors alleviated lung injury and inflammation in both mouse models and MLE-12 cells, while silencing TBC1D15 exacerbated inflammatory responses. Mechanistically, TBC1D15 overexpression dissociated mitochondria-lysosome contact duration, promoted mitophagy, and restored mitochondrial function. The protective effects of TBC1D15 were reversed by the mitophagy inhibitor Bafilomycin A1. Additionally, TBC1D15 knockdown prolonged mitochondria-lysosome contact time, resulting in worsened mitochondrial dysfunction and increased oxidative stress. Our findings indicate that SI-ALI is characterized by prolonged mitochondria-lysosome contact and impaired mitophagy. Thus, TBC1D15 overexpression presents a promising therapeutic strategy to mitigate mitochondrial dysfunction and reduce lung injury in septic conditions, suggesting potential clinical applications for SI-ALI treatment.