Diabetic kidney disease (DKD), a leading cause of end-stage renal disease (ESRD), poses a serious threat to global health. Aseptic inflammation and pyroptosis of podocytes are crucial factors contributing to the pathogenesis and progression of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a novel class of antidiabetic agents widely used in clinical settings, may exert a protective effect on podocyte injury, although the underlying mechanisms remain poorly understood. This study uses the streptozotocin (STZ) -induced DKD mouse model to further explore the mechanism by which SGLT2i protect podocytes. The results demonstrated that Canagliflozin (CANA) treatment significantly improved serum creatinine levels, 24-h urinary albumin excretion, and urinary albumin-to-creatinine ratio (UACR) in DKD mice. Additionally, CANA treatment attenuated glomerular and podocyte injury, reducing overall pathological damage. Mechanistically, CANA reduced the expression of key inflammatory markers in the renal cortex of DKD mice, including TXNIP, NLRP3, ASC, caspase-1, IL-1β, IL-18, and GSDMD. These findings suggest that CANA may be an effective therapeutic agent for DKD by inhibiting the TXNIP-NLRP3 inflammasome pathway and preventing podocyte pyroptosis.