© 2021 Elsevier LtdModerate red wine consumption has been shown to decrease the risk of cardiovascular diseases and beneficial effects on lipid metabolism and patients with type 2 diabetes mellitus (T2DM). Though there were studies on the antidiabetic effects of polyphenols, in this study we evaluated the red wine polyphenols holistically and analyzed by network pharmacology with the basis of multicomponent-multitarget paradigm. 116 compounds with a polyphenolic structure determined in red wine were listed in this study. Compounds were filtered due to their bioavailability scores and 43 compounds that met the selection criteria were further searched for their targets. The study was conducted by constructing three subgroups. These subgroups include i) all polyphenols (SG1), ii) all polyphenols except t-resveratrol (SG2), and iii) t-resveratrol (SG3). ‘Compound-Target’ network of SG1, SG2, and SG3 was merged with ‘Disease-Target' network. These common targets were subjected to DAVID database. The KEGG pathway enrichment analysis showed enrichment for FOXO signaling pathway, insulin resistance, TNF signaling pathway, PI3K-AKT signaling pathway, and HIF-1 signaling pathway that were related to T2DM. The key targets were defined as AKT1, STAT3, and IL6 using protein-protein interaction network. All 43 compounds were tested for their binding abilities to the key targets. Catechin gallate, (−)-epicatechin 3-O-gallate, rosmarinic acid, piceatannol 3′-O-glucoside, apigenin, ellagic acid, δ-viniferin, and t-resveratrol were found as prominent compounds in molecular docking studies. Our findings suggested that polyphenols in red wine could make improvements in glucose metabolism through FOXO and PI3K-AKT signaling pathway and could be protective against type 2 diabetes related complications.