The dried rhizome of Musa basjoo Sieb. et Zucc. is Rhizoma Musae. It has been used to treat diabetes in Miao medicine in China. Lupenone was isolated from Rhizoma Musae and has good anti-diabetic activity. Its mechanism of action is unclear. Diabetes is a chronic low-level systemic inflammatory disease, and lupenone has anti-inflammatory activity, but the underlying mechanism is not fully elucidated. In this study, we aimed to construct the drug-target biologic network and predict the anti-inflammatory mechanism of lupenone. The network-based pharmacologic analysis platform was used to identify the target proteins related to inflammation. Furthermore, the effects of lupenone on acute, subacute and diabetic pancreatic inflammation were evaluated. The "component-target-disease" network was constructed using Cytoscape. Lupenone could regulate transcription factor p65, NF-kappa-B inhibitor alpha, transcription factor AP-1, NF-kappa-B essential modulator, nuclear factor NF-kappa-B p105 subunit, epidermal growth factor receptor, hypoxia-inducible factor 1-alpha and other proteins related to the PI3K-Akt, Toll-like receptor and NF-kappa B signaling pathways. In addition, lupenone significantly decreased acute and subacute inflammation in mice as well as the IL-1β and IFN-γ levels in the pancreas of diabetic rats. The above results provide strong support for studying the molecular mechanism of lupenone in the treatment of diabetes from the perspective of anti-inflammation.