Atherosclerosis (AS) is a chronic inflammatory disease, and pyroptosis-a recently discovered pro-inflammatory programmed cell death process-can exacerbate these inflammatory responses. Vascular endothelial cell pyroptosis contributes to AS progression. Cathepsin B (CTSB) is a crucial member of the cysteine protease family found in lysosomes. However, its exact role in vascular endothelial cell pyroptosis remains unclear. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, inhibits pyroptosis and alleviates AS independent of its hypoglycemic effect. This study utilized oxidized low-density lipoprotein (ox-LDL) to induce pyroptosis in human umbilical vein endothelial cells (HUVECs) and investigated the effect of this process. The study revealed that ox-LDL induced HUVEC pyroptosis in a concentration-dependent manner, resulting in Na+ and Ca2+ overload, lysosomal damage, and increased CTSB release into the cytosol. Lentiviral vectors were used to overexpress or silence CTSB; subsequent analysis revealed that CTSB promotes NLRP3-mediated pyroptosis through nuclear factor kappa B (NF-kappa B) activation. Finally, we found that DAPA attenuated HUVEC pyroptosis by inhibiting the NF-kappa B/NLRP3 pathway and decreasing the expression of CTSB. This effect may be attributed to its ability to alleviate lysosomal damage caused by Na+-Ca2+ overload, thereby reducing CTSB release into the cytosol.