In order to investigate the therapeutic effects and mechanisms of Huangqi Gegen Decoction (HGD) on diabetic nephropathy (DN) in rats based on network pharmacology and TLR4/NF-κB signaling pathway. The drugs and disease targets were screened through TCMSP and other databases, and the core PPIs were mined. GO and KEGG enrichment analyses were conducted. Male SD rats were randomly divided into normal group, DN group, HGD low-dose, middle-dose, high-dose groups (2.5, 5, 10 g/kg) and metformin hydrochloride group (0.15 g/kg)， which were induced to form the DN model by a high-fat high-sugar diet combined with streptozotocin. The drug-administered groups were given the corresponding drugs by gavage, while the normal group and the model group were given distilled water by gavage, for 8 consecutive weeks. Fasting blood glucose (FBG) were measured; the pathological changes of kidney tissue were observed; the levels of serum ET-1, Ang-Ⅰ, Ang-ⅠⅠ, IL-1β, IL-6, and TLR4, NF-κB p65 in kidney tissue were determined; and the positive expression rate of TGF-β1 protein in kidney tissue was detected. Network pharmacology identified 23 active compounds and 182 target genes for HGD, along with 4004 DN genes and a shared set of 131 genes between HGD and DN, with IL-6 and IL-1β serving as core PPIs. Significant enrichment was observed in the TLR4/NF-κB pathway. Experimental verification showed that compared with the normal group, the FBG of the DN group rats significantly increased (P<0.05); the glomerular volume increased, the basement membrane thickened, the mesangial matrix increased, the tubular epithelial cells swelled, accompanied by infiltration of inflammatory cells; the expression levels of serum ET-1, Ang-Ⅰ, Ang-ⅠⅠⅠ, IL-6, IL-1β and renal tissue TLR4, NF-κB p65, TGF-β1 were significantly increased (P<0.05). Compared with the DN group, the FBG of the HGD high-dose group rats significantly decreased (P<0.05); the pathological changes in the kidney were significantly alleviated; the expression levels of serum ET-1, Ang-Ⅰ, Ang-ⅠⅠ, IL-6, IL-1β and renal tissue TLR4, NF-κB p65, TGF-β1 were significantly reduced (P<0.05). HGD has a better therapeutic effect on DN rats, and the mechanism may be related to regulating the TLR4/NF-κB signaling pathway.