Objective To investigate changes in the pro-inflammatory mediator S100A8/9 and NLRP3/ Caspase-1/IL-1β pathway in a rat kidney-aging model induced by D-galactose. Methods Twelve SD rats were divided into control and D-galactose groups, and injected subcutaneously in the back of the neck with D-galactose (150 mg/kg) to establish a rat model of kidney aging. Kidney samples were collected under anesthesia after 8 weeks. Kidneys were stained for senescence-associated beta-galactosidase (SA-β-Gal), mRNA expression levels of the aging related genes p21, p16, and p53 were detected by quantitative reverse transcription-polymerase chain reaction(qRT PCR), and histopathological changes were observed by hematoxylin-eosin(HE) and Masson staining. Serum urea nitrogen and creatinine, and catalase (CAT), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and malondialdehyde (MDA) levels in the kidney tissues were detected. Reactive oxygen species (ROS) were detected by dihydroethdium staining and protein expression levels of collagen Ⅲ, α-smooth muscle actin (α-SMA), Protein expression of S100A8/9 was detected by immunofluorescence, and transforming growth factor (TGF)-β1 levels in kidney tissues and key factors in the NLRP3/Caspase-1/IL-1β inflammatory pathway were detected by Western Blot. A renal senescence model using HK-2 cells was constructed using H₂ O₂ in vitro, and expression levels of the senescence proteins p21 and p16 and mRNA expression levels of the inflammatory factors IL-18 and tumor necrosis factor-α(TNF-α) were detected. Cell senescence was observed by SA-β-Gal staining. The effects of the S100A8/9 inhibitor paquinimod on expression levels of S100A8/9 and NLRP3/Caspase-1/IL-1β pathway-related proteins in the aging model were also detected. Results mRNA levels of the aging genes p21, p16, and p53 in kidney tissues were significantly increased in rats in the D-galactose group compared with the control group (P<0.01), and SA-β-Gal staining showed a significant increase in senescent cells (P<0.01). Serum blood urea nitrogen and creatinine levels increased (P<0.05), CAT, GSH-PX, and SOD activities decreased (P<0.01), while MDA activity increased in the D-galactose group (P<0.01). Collagen Ⅲ, α-SMA, and TGFβ1 expression and the ROS content in tissues increased (P<0.05). Glomeruli were atrophied or absent in the D-galactose group, the lumens of the renal sacs and renal tubules were enlarged, the nuclei were deeply stained and constricted, and numerous collagen fibers were deposited. Levels of S100A8 and S100A9 protein (P<0.01), as well as NLRP3, Caspase-1, and IL-1β increased (P < 0.05). Paquinimod alleviated HK-2 cell senescence and decreased expression levels of the senescence proteins p21 and p16, and mRNA levels of the inflammatory factors IL-18 and TNF-α (P<0.05, P<0.01). The number of senile cells was also decreased, shown by SA-β-Gal staining (P<0.01). Paquinimod also inhibited the protein expression of S100A8 and S100A9 (P<0.01) and NLRP3, Caspase-1, and IL-1β (P<0.05 or P<0.01). Conclusions S100A8/9 participates in the chronic inflammatory response by activating the NLRP3/Caspase-1/IL1β pathway, thereby promoting D-galactose-induced renal aging.