The intervention mechanism of astragaloside IV (ASIV) on diabetic nephropathy(DN) rats was explored through network pharmacology and molecular docking, and its intervention effect on DN rats through the adenosine 5'-monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1)/nuclear factor κB (NF-κB) signaling pathway was verified by Western blot and RT-qPCR. Network pharmacology and molecular docking were used to screen the potential targets of ASIV intervention on DN. SD rats were induced to establish a DN injury model by high-fat diet combined with streptozotocin injection. The rats were divided into normal control group, model group, metformin group,40 mg/kg ASIV group, and 80 mg/kg ASIV group, with six rats in each group. HE and Masson staining were used to evaluate the renal pathological changes, and the expression levels of AMPK, SIRT1 and NF-κB were detected by Western blot and RT-qPCR. The results of network pharmacology and molecular docking showed that the AMPK/SIRT1/NF-κB signaling pathway was the potential key mechanism of ASIV intervention on DN. In the animal experiments, after ASIV intervention, the infiltration of inflammatory cells and the deposition of collagen fibers were improved. Compared with the model group, both the 40 mg/kg ASIV group and the 80 mg/kg ASIV group could significantly activate AMPK (P < 0.05), increase the expression of SIRT1 (P < 0.05), and inhibit the expression of NF-κB (P < 0.05). The results of network pharmacology and animal experiments indicated that ASIV improved the renal function and histopathological damage of DN rats by regulating the AMPK/SIRT1/NF-κB signaling pathway, providing theoretical support for its potential as a therapeutic drug for DN.