Objective To investigate whether liraglutide plays a protective role in diabetic nephropathy (DN) by inhibiting the activation of NOD-like receptor pyrin domain containing 3 (NLRP3). Methods Twenty-two male Wistar rats (4 weeks old) were randomly divided into normal control group (n=6), liraglutide group (n=8) and normal saline group (n=8). After DN model was established, the rats of the liraglutide group were subcutaneously injected with 200 μg/(kg·d) liraglutide, those from the normal saline group were subcutaneously injected with same volume of normal saline, and those of the normal control group received no treatment. After 4 weeks′ treatment, body mass, 24 h urinary total protein (UTP), fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), blood urea nitrogen (BUN), serum creatinine (SCr) and other biochemical indexes were detected. Hematoxylin-eosin(HE) staining was used to observe the pathological changes of renal tissue. The expression of NLRP3 inflammasome-related proteins in renal tissue was measured by Western blot, and the serum levels of interleukin-18 (IL-18) and interleukin-1β (IL-1β) were detected by enzyme-linked immunosorbent assay (ELISA). SPSS statistics 26.0 and Graph Prism 9.0 software were used for analysis and mapping. One-way ANOVA was employed for intergroup comparison for measurement data, and Tukey test was adopted for intra-group comparison. Results Liraglutide intervention improved the levels of FBG, UTP, BUN, SCr, TC and TG when compared with those in normal saline group (P<0.01). Pathological observation displayed that normal structure of glomeruli and tubules were observed in the normal control group, increased glomerular volume and structure, extramembranous matrix, and significant thickening in basement membrane were seen in the normal saline group, and the pathological changes of the kidneys were alleviated in the liraglutide group. Western blot assay indicated that the protein expression levels of NLRP3 inflammasome-related proteins were significantly lower in the liraglutide group than the normal saline group. The results of ELISA showed that the levels of IL-18 and IL-1β were significantly increased in the normal saline group, but decreased after liraglutide intervention. Conclusion Liraglutide alters disease progression in DN rats, which may be related to its inhibition of NLRP3 inflammasome activation.