Background: Alpiniae oxyphyllae-Saposhnikovia divaricata (AS), a traditional Chinese dietary supplement, exhibits potential therapeutic effects against diabetic kidney disease (DKD), though its active compounds and mechanisms require elucidation. Methods: Animal experiments integrated with UHPLC-QE-MS, bioinformatics, and experimental validation were employed to investigate AS’s pharmacodynamic basis against DKD. Results: Thirty-nine compounds were identified in AS, including four key flavonoids (daidzein, kaempferol, tectoridin, baicalin). Bioinformatics screening revealed 516 potential AS targets from PubChem/TCMSP/ETCM databases. Analysis of the GEO dataset (GSE30529) identified 482 DKD-related differentially expressed genes (DEGs). Venny 2.1 analysis yielded 42 co-DEGs and 6 co-core DEGs. Functional enrichment (GO/KEGG/GSEA) demonstrated AS’s modulation of apoptosis and extracellular matrix (ECM) pathways via these DEGs. ROC profiling and renal single-cell sequencing highlighted FOS as a specific regulator of podocyte apoptosis in DKD. Molecular docking confirmed stable binding between the four flavonoids and FOS. Experimentally, AS significantly suppressed expression of ECM-related proteins (Col-IV, LN, IL-6, IL-17) and pro-apoptotic proteins (Bax, Caspase-3), while restoring anti-apoptotic Bcl-2 levels and inhibiting phosphorylation of MEK4, JNK1, c-Jun, and FOS in DKD mice. Conclusion: This study elucidates that AS alleviates DKD by inhibiting the MAPK/FOS pathway, thereby attenuating podocyte apoptosis and ECM accumulation. These findings establish a foundation for targeted AS therapy in DKD.