〔Abstract〕 Objective To explore the effects and mechanisms of NADPH oxidase 4(NOX4) and nucleotide-binding oligomeric structural domain protein-like receptor protein 3(NLRP3) inflammasome on aging-associated renal injury in mice. Methods The 6, 16, 20, and 24-month-old mice were used in this study. The levels of serum creatinine(SCr) and blood urea nitrogen(BUN) were detected by the kit. Frozen sections of kidney tissue were used to detect the levels of β-Galactosidase(β-Gal) and reactive oxygen species(ROS). The pathological changes of the kidney were observed by H&E, PAS, and Masson staining. The expressions of collagen Ⅳ and NLRP3 were detected by immunohistochemistry. Western blot was used to detect the expression of related proteins in the NOX4-NLRP3 signaling pathway in kidney tissues. Results The results showed that, compared with 6-month-old mice, the levels of BUN and SCr in serum, β-Gal activity, and ROS level in the renal cortex increased, the glomerular and tubular injury was mild, and there was no obvious renal fibrosis change in 16-month-old mice. However, in 20 and 24-month-old mice, these indexes increased, the damage of glomeruli and renal tubules increased, and renal fibrosis appeared. In addition, expression of NOX4 and NLRP3 inflammasome-associated proteins mediating ROS production was upregulated in the kidneys of 20-and 24-month-old mice. Conclusion The NOX4-NLRP3 signaling pathway may activate and promote renal aging and renal fibrosis during aging.