Background and Purpose: Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes that has limited treatment options. NLRP3-initiated pyroptosis is tightly implicated in DN progression. Mitochondrial ROS (mtROS) are a critical trigger of NLRP3 activation. Syringaresinol, a natural plant-derived polyphenolic compound, possesses strong antioxidant properties. However, whether syringaresinol provides renoprotection in DN remains unclear. Experimental Approach: The renoprotection effects of syringaresinol were investigated in streptozotocin-induced wild-type and Nrf2-KO mice. The underlying mechanism of syringaresinol on DN was assessed in diabetic renal tissues and high glucose-stimulated primary renal tubular epithelial cells as well as glomerular mesangial cells HBZY-1. Key Results: Syringaresinol treatment ameliorated renal structural and functional changes in streptozotocin-induced diabetic mice, including renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, podocyte foot process effacement and albuminuria. Mechanistically, syringaresinol prevented the NLRP3/Caspase-1/GSDMD pyroptosis pathway and promoted Nrf2 expression and nuclear transfer in both diabetic renal tissues and high glucose-stimulated primary renal tubular epithelial cells as well as HBZY-1 cells. After that, the nuclear-transferred Nrf2 upregulated the antioxidant genes HO-1 and MnSOD, thereby effectively improving mitochondrial dysfunction and decreasing excess cytosolic ROS and mtROS. Most importantly, knockout of Nrf2 abolished the syringaresinol-mediated renoprotection and antioxidant effects and subsequent mtROS overproduction, resulting in the activation of NLRP3/Caspase-1/GSDMD signaling. Conclusion and Implications: Syringaresinol attenuated diabetic renal lesions by preventing the NLRP3/Caspase-1/GSDMD pyroptosis pathway in an Nrf2-dependent manner. This suggests that syringaresinol may represent promising therapeutic options for DN.