Diabetic kidney disease (DKD) is a severe metabolic disorder that typically results from diabetes mellitus and culminates in chronic kidney disease and renal failure. It has been reported that Holothuria leucospilota polysaccharide (HLP) has an improvement effect on type 2 diabetes mellitus (T2DM) rats. This study aimed to explore the impact of HLP on DKD further and reveal its mechanism. The spontaneous Goto-Kakizaki (GK) rats were used as a model of the DKD group, and Wistar rats were used as a normal control group, treated with intragastric administration for 4 weeks. The results showed that after HLP intervention, the renal index was reduced. Scr, BUN, and UA levels increased in the DKD group, and the HLP-H group was significantly decreased by 15.44 μmol/L, 1.11 mmol/L, and 0.08 mmol/L (p <
0.05). HLP also alleviated renal pathological damage and kidney fibrosis, decreased MIF, CD74, and IL-6 mRNA expression levels, enhanced PI3K, AKT, and PCX levels. These results indicated that HLP effectively relieved DKD by regulating inflammation and metabolism.