Objective This study aims to investigate the regulatory effects of astragaloside IV on the HIF-1α signaling pathway in diabetic nephropathy and explore its potential therapeutic mechanisms. Methods: The model of diabetes nephropathy was established by injecting streptozotocin, qRT-PCR and Western blotting were used to assess the effects of astragaloside IV on the expression of Collagen I, α-SMA. Differential gene enrichment analysis was performed on the datasets of diabetic kidney disease patients downloaded from the GEO database, and activated pathways were screened out. Meanwhile, immunohistochemistry and flow cytometry were used to evaluate the effects of Astragaloside IV in reducing renal fibrosis, inflammatory response, and regulating macrophage polarization. Finally, the key role of the HIF-1α pathway in DN was further validated using the HIF-1α inhibitor LW6. Results: The results showed that the GEO database showed that HIF-1 α/NF-κB signaling pathway was activated in patients with diabetes nephropathy. The results showed that astragaloside IV treatment significantly inhibited the expression of HIF-1α and its downstream fibrosis-related molecules in the diabetic nephropathy mouse model, reducing renal fibrosis and inflammatory responses. Astragaloside IV also promoted M2 macrophage polarization while suppressing M1 macrophage activation. The critical role of the HIF-1α pathway in the pathology of DN was further confirmed through experiments using the HIF-1α inhibitor LW6. Conclusion: This study demonstrates that astragaloside IV significantly mitigates fibrosis and inflammation in diabetic nephropathy by regulating the HIF-1α signaling pathway and promotes favorable macrophage polarization.