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Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The inflammatory response plays a critical role in the process of DN. ZiShenWan (ZSW) is a classical Chinese medicinal formula with remarkable clinical therapeutic effects on DN, but its pharmacological action mechanisms remain unclear. Methods: In this study, a network pharmacology approach was applied to investigate the pharmacological mechanism of ZSW in DN therapy. The “drug-ingredient-target” network for ZSW in DN treatment was established with Cytoscape software based on candidate active components of ZSW and targets in DN treatment obtained from databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed with the key targets. Because inflammation is important in DN, the key targets and signaling pathways associated with the anti-inflammatory, renoprotective mechanism of ZSW were partially validated in db/db mice. Results: A total of 56 active ingredients in ZSW and 166 DN-related targets were selected from databases. Various related genes and pathways participate in the inflammatory response. ZSW markedly alleviated renal injury in db/db mice by inhibiting the exaggerated release of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor -ɑ (TNF-ɑ), monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-β1 (TGF-β1) and regulating the p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling pathways. Conclusions: Network pharmacology analysis demonstrated that ZSW achieved therapeutic renoprotective effects in DN by alleviating the inflammatory response via regulation of multiple targets and signaling pathways.