Acute lung injury (ALI) is the leading cause of bacterial sepsis-related death because of disrupted pulmonary endothelial barrier, resulting in protein-rich pulmonary oedema, an influx of pro-inflammatory cells and refractory hypoxaemia. Several studies have reported that C3a levels are significantly higher in organs with sepsis and their peripheral organs and are closely associated with organ dysfunction and poor prognosis in sepsis. However, the role of the C3a complement in sepsis ALI remains unclear. Therefore, this study aimed to investigate the important role and mechanism of C3a in preventing the occurrence of pyroptosis (a pro-inflammatory form of cell death) to protect the lung endothelial cells (ECs) in sepsis-induced ALI. A septic mouse model was established with cecal ligation and puncture (CLP), which demonstrated that C3a mediated EC pyroptosis through its C3aR receptor. Furthermore, inhibition of the C3a-C3aR axis could block both NLRP3/caspase-1 and caspase-11 pathways, thus preventing pulmonary EC from pyroptosis. These results indicate that inhibition of the C3A-C3AR complement axis can inhibit pulmonary vascular EC pyroptosis, a potential target for the treatment of ALI.