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Coronopus didymus (Brassicaceae) is a medicinal herb valued for its anti-inflammatory and hyperlipidemic properties; however, its antidiabetic potential remains entirely unexplored. Furthermore, despite the known therapeutic benefits of Azadirachta indica and the bioflavonoid quercetin, their evaluation in combination with C. didymus has never been investigated. To address this knowledge gap, this study pioneers the evaluation of C. didymus, A. indica, and quercetin-individually and as a novel combined formulation for the management of type 2 diabetes mellitus (T2DM). We employed an integrated approach utilizing in silico network pharmacology and molecular docking (targeting NOS3, AKT1, and PPARG), in vitro bioassays (antioxidant, α-amylase inhibition, hemolytic, and anticancer), and in vivo evaluation in streptozotocin-nicotinamide (STZ-NA)-induced diabetic mice. Network screening identified 100 overlapping targets between the quercetin and T2DM, prioritizing 15 key hub targets via protein-protein interaction and KEGG pathway enrichment analyses. Molecular docking confirmed strong binding affinities of the lead compounds to NOS3, AKT1, and PPARG. In vitro assays validated robust antioxidant, α-amylase inhibitory, and anticancer activities, while maintaining a safe hemolytic profile. In vivo trials demonstrated that while individual treatments effectively lowered blood glucose, the combined formulation exhibited superior hepatoprotective efficacy, profoundly reducing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (p < 0.0001) toward baseline control levels compared to individual plant extracts, alongside enhancing serum antioxidants and ameliorating histopathological damage in hepatic and intestinal tissues. In conclusion, this study bridges a critical gap in ethnopharmacology by identifying the antidiabetic potential of C. didymus and demonstrating that its combination with A. indica and quercetin offers a potent, distinct hepatoprotective advantage, highlighting its potential as a targeted nutraceutical approach for managing T2DM and its associated hepatic complications.