Grape pomace is an important source of flavonoid glucosides, which are attractive for their bioactivities. In this innovative approach, microwave and enzyme-assisted extraction were used as a suitable alternative for obtaining compounds without significantly affecting the composition and bioactivity. This work aimed to apply green-technologies to obtain flavonoids from grape pomace with potential antioxidant activity and the effect of flavonoid glucoside on antihyperglycemic activity. The extracts were determined for phenolic compounds (TPC) and flavonoids (TFC), free radical scavenging capacity by DPPH, and identification by HPLC-MS. Antihyperglycemic activity analysis by in silico molecular docking with phenolic compounds and pancreatic α-amylase. TPC presented an extraction range of 41.56–90.06 mg GAE/g ds, TFC 14.63–38.31 mg QE/g ds, and a radical scavenging capacity of 59.96%–85.43%. The extracts obtained by enzymes (pectinase) were characterized by higher extraction yield and bioactivity. The molecular docking of pancreatic α-amylase showed binding energy lower than −8.0 kcal/mol and molecular interaction of the catalytic amino acids with flavonoids 3-O-glucoside. In conclusion, flavonoid glucosides from grape pomace demonstrate potential as a functional food additive, neutralizing free radicals and regulating postprandial blood glucose levels. Harnessing processed plants' therapeutic potential for human health while also generating agro-industrial sustainability.