Objective To study the effect and possible mechanism of Zhenwu Decoction on renal inflammatory injury in mice with spleen-kidney yang deficiency-type diabetic nephropathy. Methods Mice (db/ m mice) were treated with rhubarb solution and hydrocortisone to induce a db/ db mouse spleen and kidney yang deficiency syndrome model. Mice in the blank control group were untreated. After successful modeling, the db/ db mice were divided randomly into a model control group, irbesartan group (25 mg/ kg), and high-, medium-, and low-dose Zhenwu Decoction groups (33. 8, 16. 9, 8. 45 g/ kg, respectively) (n= 15 per group). Mice in all groups except the blank control and model control groups were given the corresponding drugs by gavage once a day for 8 weeks. Mice in the blank control and model control groups received the same volume of normal saline. Traditional Chinese medicine syndrome scores were measured in each group. Fasting blood glucose ( FBG), urinary creatinine ( Ucr), and 24 h urinary protein (24 h UTP) were measured. Testosterone (T), triiodothyronine (T3), tetraiodothyronine (T4), estradiol (E2), interleukin (IL)-1β, and IL-18 levels in renal tissues were measured by enzyme-linked immunosorbent assay. Histopathological changes in the kidneys were observed by hematoxylin/ eosin staining. NOD-like receptor thermal protein domain associated protein 3 ( NLRP3), Apoptosis-associated speckle-like protein(ASC), Cysteinyl aspartate specific proteinase-1(Caspase-1) mRNA and protein expression levels in renal tissues were detected by Real-time quantitative PCR ( RT-qPCR) and Western Blot. Results Mice in the model control group showed symptoms of spleen-kidney yang deficiency, such as anorexia, fatigue, and decreased, loose stools compared with the blank control group, while FBG, 24 h UTP, IL-1β, IL-18, and E2 were significantly increased (P< 0. 05) and T, T3, T4, and Ucr were significantly decreased (P< 0. 05). Renal pathology showed glomerular hypertrophy, and glomerular mesangial and basal thickening. Protein and mRNA levels of NLRP3, ASC, and caspase-1 in renal tissue were significantly increased (P< 0. 05). In contrast, mice in the high-, medium-, and low-dose Zhenwu Decoction groups had increased body weight, activity, and stool molding compared with the model control group, as well as significantly increased levels of T, T3, T4, and Ucr (P< 0. 05) and significantly decreased levels of 24 h UTP, IL-1β, IL-18, and E2 (P< 0. 05). In addition, pathological damage to the renal tissue was significantly improved and the protein and mRNA expression levels of NLRP3, ASC, and Caspase-1 were significantly decreased in all treatment groups (P< 0. 05). Conclusions Zhenwu Decoction can improve the general condition and renal function, and reduce the inflammatory reaction and renal pathological injury in db/ db mice with spleen-kidney yang deficiency, via a mechanism possibly related to inhibition of the NLRP3/ ASC/ Caspase-1 pathway.