This study aims to systematically investigate the renoprotective mechanisms of Salvia miltiorrhiza (SM;丹参) in diabetic nephropathy (DN) through an integrative approach combining network pharmacology, molecular docking, and experimental validation. Bioactive constituents and pharmacological targets of Salvia miltiorrhiza were identified through systematic bioinformatics mining and protein-protein interaction (PPI) network analysis. Molecular docking simulations validated interactions between key components and targets. Streptozotocin (STZ)-induced DN mice were treated with Salvia miltiorrhiza to assess renal function, oxidative stress, inflammatory markers, and PI3K/AKT/mTOR pathway modulation. Network pharmacology identified 62 overlapping targets between Salvia miltiorrhiza and DN, with TNF, AKT1, and EGFR as core targets. Molecular docking demonstrated strong binding affinities (e.g., luteolin-TNF: −9.2 kcal/mol). In vivo, Salvia miltiorrhiza significantly reduced hyperglycemia, proteinuria, serum creatinine (Scr), and blood urea nitrogen (BUN), histopathology demonstrated reduced glomerulosclerosis and fibrosis, while attenuating oxidative stress and reduced serum levels of caspase-1, interleukin-18 (IL-18), and interleukin-1β (IL-1β). Western blot analysis confirmed significant reductions in phosphorylation levels of PI3K (p-PI3K), AKT (p-AKT), and mTOR (p-mTOR).  Salvia miltiorrhiza ameliorates DN progression through multi-target modulation of the PI3K/AKT pathway, suppression of inflammatory responses, and oxidative stress mitigation. These findings mechanistically validate Salvia miltiorrhiza as a pleiotropic therapeutic agent targeting DN pathophysiology, providing translational rationale for clinical development. This study provides a pharmacological foundation for repurposing Salvia miltiorrhiza as a multi-target therapeutic agent in DN management.