The present investigation aimed to evaluate the anti-diabetic effect of the well-known food plant Polygonum posumbu along with the mechanism of combining its in-vitro, in-vivo effects and UHPLC-QTOF-MS based phytochemical profiling linked with the network pharmacology. In-vitro anti-diabetic potential of the extract was determined by testing against α-amylase and α-glucosidase enzymes. The in-vivo anti-diabetic effect of the extract was investigated in STZ-induced diabetic mice. Tissue and blood samples were taken for the assessment of tissue antioxidant capacity, biochemical markers and HbAc1 level estimation. Pancreas was subjected to histopathology examination. The anti-diabetic mechanism was further explored using UHPLC-QTOF-MS based metabolomic analysis combined with network pharmacology. The in-vitro findings showed that the extract has more selectivity towards α-amylase as compared to α-glucosidase. Administration of extract found to stimulate glucose utilization in OGTT study. Extract treated group also showed significant reduction in blood glucose level on 14th day. HbA1c, AST/GOT, ALP, creatinine, and urea level were also normalized in extract treated group. This is further evident by histopathology observation of pancreatic islets cells morphology. Moreover UHPLC-QTOF-MS based metabolomic study combined with network pharmacology analysis identified EGFR, SRC, IGF1R, MET, MMP9, ESR1, KDR, MMP2, ESR2, and SMAD3 as key targets for showing anti-diabetic activity. The findings integrating the phytochemical and therapeutic potential through the in-vitro, in-vivo and network pharmacology analysis of P. posumbu extract against diabetes suggested that the herb could be a good source for further development of functional food for the management of diabetic complications.